Imidazole compounds

ABSTRACT

Imidazole compounds, compositions, and methods of using them in leukocyte recruitment inhibition, in modulating H 4  receptor expression, and in treating conditions such as inflammation, H 4  receptor-mediated conditions, and related conditions.

This application is a divisional of U.S. patent application Ser. No.11/704,123, filed on Feb. 8, 2007, which is a divisional of U.S. patentapplication Ser. No. 11/088,488, filed on Mar. 24, 2005 now U.S. Pat.No. 7,253,200, which in turn claims the benefit of U.S. provisionalpatent application Ser. No. 60/556,356, filed on Mar. 25, 2004, each ofwhich is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to novel, pharmaceutically active, heterocycliccompounds, more particularly imidazole compounds, and methods of usingthem to treat or prevent disorders and conditions mediated by thehistamine H₄ receptor.

BACKGROUND OF THE INVENTION

Histamine was first identified as a hormone (Barger, G. and H. H. Dale,J. Physiol. (London) 1910, 41:19-59) and has since been demonstrated toplay a major role in a variety of physiological processes, including theinflammatory “triple response” via H₁ receptors (Ash, A. S. F. and H. O.Schild, Br. J. Pharmac. Chemother. 1966, 27:427-439), gastric acidsecretion via H₂ receptors (Black, J. W. et al., Nature 1972,236:385-390), and neurotransmitter release in the central nervous systemvia H₃ receptors (Arrang, J.-M. et al., Nature 1983, 302:832-837) (forreview see Hill, S. J. et al., Pharmacol. Rev. 1997, 49(3):253-278). Allthree histamine receptor subtypes have been demonstrated to be membersof the superfamily of G protein-coupled receptors (Gantz. I. et al.,Proc. Natl. Acad. Sci. U.S.A. 1991, 88:429-433; Lovenberg, T. W. et al.,Mol. Pharmacol. 1999, 55(6):1101-1107; Yamashita, M. et al., Proc. Natl.Acad. Sci. U.S.A. 1991, 88:11515-11519). There are, however, additionalfunctions of histamine that have been reported, for which no receptorhas been identified. For example, in 1994, Raible et al. demonstratedthat histamine and R-α-methylhistamine could activate calciummobilization in human eosinophils (Raible, D. G. et al., Am. J. Respir.Crit. Care Med. 1994, 149:1506-1511). These responses were blocked bythe H₃-receptor antagonist thioperamide. However, R-α-methylhistaminewas significantly less potent than histamine, which was not consistentwith the involvement of known H₃ receptor subtypes. Therefore, Raible etal. hypothesized the existence of a novel histamine receptor oneosinophils that was non-H₁, non-H₂, and non-H₃. Most recently severalgroups (Oda, T. et al., J. Biol. Chem. 2000, 275(47):36781-36786; Liu,C. et al., Mol. Pharmacol. 2001, 59(3):420-426; Nguyen, T. et al., Mol.Pharmacol. 2001, 59(3):427-433; Zhu, Y. et al., Mol. Pharmacol. 2001,59(3):434-441; Morse, K. L. et al., J. Pharmacol. Exp. Ther. 2001,296(3):1058-1066) have identified and characterized a fourth histaminereceptor subtype, the H₄ receptor. This receptor is a 390 amino acid,seven-transmembrane, G protein-coupled receptor with approximately 40%homology to the histamine H₃ receptor. In contrast to the H₃ receptor,which is primarily located in the brain, the H₄ receptor is expressed atgreater levels in eosinophils and mast cells, among other cells, asreported by Liu et al. (infra) and Hofstra et al. (J. Pharmacol. Exp.Ther. 2003, 305(3):1212-1221). Because of its preferential expression onimmunocompetent cells, this H₄ receptor is closely related with theregulatory functions of histamine during the immune response.

A biological activity of histamine in the context of immunology andautoimmune diseases is closely related with the allergic response andits deleterious effects, such as inflammation. Events that elicit theinflammatory response include physical stimulation (including trauma),chemical stimulation, infection, and invasion by a foreign body. Theinflammatory response is characterized by pain, increased temperature,redness, swelling, reduced function, or a combination of these.

Mast-cell de-granulation (exocytosis) releases histamine and leads to aninflammatory response that may be initially characterized by ahistamine-modulated wheal and flare reaction. A wide variety ofimmunological stimuli (e.g., allergens or antibodies) andnon-immunological (e.g., chemical) stimuli may cause the activation,recruitment, and de-granulation of mast cells. Mast-cell activationinitiates allergic (H₁) inflammatory responses, which in turn cause therecruitment of other effector cells that further contribute to theinflammatory response. The histamine H₂ receptors modulate gastric acidsecretion, and the histamine H₃ receptors affect neurotransmitterrelease in the central nervous system.

Modulation of H₄ receptors controls the release of inflammatorymediators and inhibits leukocyte recruitment, thus providing the abilityto prevent and/or treat H₄-mediated diseases and conditions, includingthe deleterious effects of allergic responses such as inflammation.Compounds according to the present invention have H₄ receptor modulatingproperties. Compounds according to the present invention have leukocyterecruitment inhibiting properties. Compounds according to the presentinvention have anti-inflammatory properties.

Examples of textbooks on the subject of inflammation include Gallin, J.I. and R. Snyderman, Inflammation: Basic Principles and ClinicalCorrelates, 3^(rd) Edition, (Lippincott Williams & Wilkins,Philadelphia, 1999); V. Stvrtinova, V. et al., “Inflammation and Fever”,Pathophysiology Principles of Diseases (Textbook for Medical Students,Academic Press, 1995); Cecil et al., Textbook Of Medicine, 18^(th)Edition (W.B. Saunders Company, 1988); and Steadmans Medical Dictionary.

Background and review material on inflammation and conditions relatedwith inflammation can be found in articles such as the following:Nathan, C. Nature 2002, 420:846-852; Tracey, K. J. Nature 2002,420:853-859; Coussens, L. M. and Z. Werb, Nature 2002, 420:860-867;Libby, P. Nature 2002, 420:868-874; Benoist, C. and D. Mathis, Nature2002, 420:875-878; Weiner, H. L. and D. J. Selkoe, Nature 2002,420:879-884; Cohen, J. Nature 2002, 420:885-891; Steinberg, D. NatureMedicine 2002, 8(11):1211-1217.

Inflammation herein refers to the response that develops as aconsequence of histamine release, which in turn is caused by at leastone stimulus. Examples of such stimuli are immunological stimuli andnon-immunological stimuli.

Inflammation is due to any one of a plurality of conditions such asallergy, asthma, chronic obstructed pulmonary disease (COPD),atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatorybowel diseases (including Crohn's disease and ulcerative colitis),psoriasis, allergic rhinitis, scleroderma, autoimmune thyroid diseases,immune-mediated (also known as type 1) diabetes mellitus and lupus,which are characterized by excessive or prolonged inflammation at somestage of the disease. Other autoimmune diseases that lead toinflammation include Myasthenia gravis, autoimmune neuropathies, such asGuillain-Barré, autoimmune uveitis, autoimmune hemolytic anemia,pernicious anemia, autoimmune thrombocytopenia, temporal arteritis,anti-phospholipid syndrome, vasculitides, such as Wegener'sgranulomatosis, Behcet's disease, dermatitis herpetiformis, pemphigusvulgaris, vitiligio, primary biliary cirrhosis, autoimmune hepatitis,autoimmune oophoritis and orchitis, autoimmune disease of the adrenalgland, polymyositis, dermatomyositis, spondyloarthropathies, such asankylosing spondylitis, and Sjogren's syndrome. Regarding the onset andevolution of inflammation, inflammatory diseases orinflammation-mediated diseases or conditions include, but are notlimited to, acute inflammation, allergic inflammation, and chronicinflammation.

Cited references are incorporated herein by reference.

SUMMARY OF THE INVENTION

The invention features a compound of formula (I) or (II):

wherein

-   W is, independently from other member and substituent assignments, N    or CR⁹;-   X is, independently from other member and substituent assignments, N    or CR⁹;-   Y is, independently from other member and substituent assignments,    O, NR¹⁰, or CR¹⁰R¹¹;-   Z is, independently from other member and substituent assignments, N    or CR¹²;-   n is, independently from other member and substituent assignments,    0, 1, or 2;-   each of R¹⁻² is, independently from other member and substituent    assignments, —H, —CF₃, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, optionally    substituted aryl or optionally substituted heteroaryl; or, R¹ and R²    taken together with the carbon atoms to which they are attached form    a cyclic structure Cyc1 selected from 5- or 6-membered carbocycle,    and 5- or 6-membered heterocycle with 1 heteroatom, wherein said    cyclic structure Cyc1 is, independently from other substituent    assignments, substituted with 0, 1, or 2 substituents selected from    —C₁₋₃alkyl, halo, hydroxy, amino, and —C₁₋₃alkoxy;-   each of R³⁻⁴ and R⁹ is, independently from other member and    substituent assignments, —H, —C₁₋₆alkyl, halo, —CF₃, —OCF₃, —OR^(c),    —SR^(c), —S(O)R^(c), —SO₂R^(c), Cl₁₋₄alkoxy, cyano, nitro,    —C(O)NR^(a)R^(b), —C(O)phenyl, —C(O)C₁₋₆alkyl, —S(O)C₁₋₄alkyl, or    —SO₂C₁₋₄alkyl; or, R³ and R⁴ taken together with the carbon atoms to    which they are attached form a cyclic structure Cyc2 selected from    aryl, 5- or 6-membered carbocycle, and 5- or 6-membered heterocycle    with 1 or 2 heteroatoms, wherein said cyclic structure Cyc2 is,    independently from other substituent assignments, substituted with    0, 1, or 2 substituents selected from —C₁₋₃alkyl, halo, hydroxy,    amino, and —C₁₋₃alkoxy;    -   wherein each of R^(a), R^(b) and R^(c) is, independently from        other substituent assignments, selected from H, C₁₋₄alkyl,        C₃₋₆cycloalkyl, phenyl, (C₃₋₆cycloalkyl)C₁₋₂alkyl-, benzyl and        phenethyl, or R^(a) and R^(b) taken together with the nitrogen        to which they are attached, form a 4-7 membered heterocyclic        ring HetCyc1, wherein said ring HetCyc1 has 0 or 1 additional        heteroatoms selected from O, S, >NH and >NC₁₋₆alkyl, and wherein        any phenyl, phenethyl, benzyl, alkyl or cycloalkyl moiety in any        of said R¹⁻⁴, R^(a), R^(b), R^(c), and said ring HetCyc1 is        optionally, and independently from other substituent        assignments, substituted with 1, 2 or 3 substituents selected        from C₁₋₃alkyl, halo, hydroxy, amino, and C₁₋₃alkoxy;-   R⁵ is, independently from other member and substituent assignments,    —H, —C₁₋₆alkyl, —C₁₋₄alkoxy, or hydroxy;-   each of R⁶ and R⁷ is, independently from other member and    substituent assignments, —H or —C₁₋₆alkyl, or R⁶ and R⁷ taken    together form a 5-6 membered cyclic structure Cyc3, wherein said    cyclic structure Cyc3 is a 5- or 6-membered carbocycle or a 5- or    6-membered heterocycle with 1 or 2 heteroatoms, and wherein said    cyclic structure Cyc3 is, independently from other substituent    assignments, substituted with 0, 1, or 2 substituents selected from    —C₁₋₃alkyl, halo, hydroxy, amino, and —C₁₋₃alkoxy;-   R⁸ is, independently from other member and substituent assignments,    —H or —C₁₋₄alkyl;-   each of R¹⁰ and R¹¹ is, independently from other member and    substituent assignments, —H or —C₁₋₄alkyl; or, when Y is CR¹⁰R¹¹,    R¹⁰ and R¹¹ taken together with the carbon member to which they are    attached form an optionally substituted cyclic structure Cyc4,    wherein said cyclic structure Cyc4 is a 3- to 6-membered carbocycle    or a 3- to 6-membered non-aromatic heterocycle with 0 or 1    additional heteroatoms, or CR¹⁰R¹¹ is C═O;-   R¹² is, independently from other member and substituent assignments,    —H, —C₁₋₄alkyl, hydroxy, or —C₁₋₄alkoxy;    and enantiomers, diastereomers, racemates, tautomers, hydrates,    solvates thereof, and pharmaceutically acceptable salts, amides or    esters thereof;    with the following provisos:    when Y is O or NR¹⁰, then Z is CR¹² and R⁵ is not hydroxy or    —C₁₋₄alkoxy;    when Z is N, Y is CR¹⁰R¹¹;    when R¹ and R² are both —H, Y is CH₂, and R⁸ is methyl, then R⁵ is    not hydroxy.

Embodiments of compounds of formulae (I) and (II) are modulators of theH₄ receptor. Embodiments of this invention comprise mixtures ofcompounds of formulae (I) and (II).

Isomeric forms of the compounds of formulae (I) and (II), and of theirpharmaceutically acceptable salts, amides and esters, are encompassedwithin the present invention, and reference herein to one of suchisomeric forms is meant to refer to at least one of such isomeric forms.One of ordinary skill in the art will recognize that compounds accordingto this invention may exist, for example, in a single isomeric formwhereas other compounds may exist in the form of a regioisomericmixture.

Whether stated explicitly or not in any part of the written descriptionand claims, it is understood that each substituent and member assignmentin the context of this invention is made independently of any othermember and substituent assignment, unless stated otherwise. By way of afirst example on substituent terminology, if substituent S¹ _(example)is one of S₁ and S₂, and substituent S² _(example) is one of S₃ and S₄,then these assignments refer to embodiments of this invention givenaccording to the choices S_(example) is S₁ and S² _(example) is S₃; S¹_(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ and S²_(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent R assignments described herein. The foregoing conventiongiven herein for substituents extends, when applicable, to members suchas X, Y, Z, and W, and the index n.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent R assignments described herein. The foregoing conventiongiven herein for substituents extends, when applicable, to members suchas X, Y, Z, and W, and the index n.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

When any variable referring to a substituent, compound member or index,occurs more than once, the full range of assignments is meant to applyto each occurrence, independently of the specific assignment(s) to anyother occurrence of such variable. For each occurrence of a variable, itis understood that such an assignment is made independently from othermember and substituent assignments.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B-, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

The present invention also features methods for inhibiting H₄ receptoractivity with such compounds, pharmaceutical compositions containingsuch compounds, and methods of using such compositions in the treatmentor prevention of conditions that are mediated by the H₄ receptor, suchas inflammation. Compounds according to the present invention andderivatives thereof can also be used as reference compounds in assays toassess H₄ receptor modulating characteristics in light of one or morefactors such as receptor inhibition, toxicity, bioavailability, andprotein binding capability.

Pharmaceutical compositions according to the present invention includeat least one of the compounds of the present invention. If more than oneof such compounds is included in a composition, the therapeuticallyeffective amount may be a jointly effective amount. As such inhibitorsof H₄ receptor activity, compounds and compositions according to thepresent invention are useful in the prevention, inhibition, or treatmentof H₄ receptor-mediated conditions, such as inflammation.

The invention also features a pharmaceutical composition for treating orpreventing an H₄ receptor-mediated condition in a subject, comprising atherapeutically effective amount of at least one H₄ receptor modulatorselected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates, tautomers, hydrates, solvates thereof,pharmaceutically acceptable salts, amides and esters thereof. Inaddition, the invention features a pharmaceutical composition forinhibiting leukocyte recruitment in a subject, comprising atherapeutically effective amount of at least one leukocyte recruitmentinhibitor selected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates, tautomers, hydrates, solvates thereof,pharmaceutically acceptable salts, amides and esters thereof. Theinvention additionally features an anti-inflammatory composition,comprising a therapeutically effective amount of at least oneanti-inflammatory compound selected from compounds of formulae (I) and(II), enantiomers, diastereomers, racemates, tautomers, hydrates,solvates thereof, pharmaceutically acceptable salts, amides and estersthereof.

The invention features methods for treating or preventing inflammationin a subject, comprising administering to the subject in connection withan inflammatory response a pharmaceutical composition that comprises atherapeutically effective amount of at least one anti-inflammatorycompound selected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates, tautomers, hydrates, solvates thereof,pharmaceutically acceptable salts, amides and esters thereof. Theinvention also features methods for treating or preventing an H₄receptor-mediated condition in a subject, comprising administering tothe subject a pharmaceutical composition that comprises atherapeutically effective amount of at least one H₄ receptor modulatorselected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates, tautomers, hydrates, solvates thereof,pharmaceutically acceptable salts, amides and esters thereof. Inaddition, the invention features methods for modulating an H₄ receptorexpression, comprising exposing an H₄ receptor to at least one compoundselected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates, tautomers, hydrates, solvates thereof,pharmaceutically acceptable salts, amides and esters thereof.Furthermore, the invention features methods for inhibiting leukocyterecruitment in a subject, comprising administering to the subject apharmaceutical composition that comprises a therapeutically effectiveamount of at least one leukocyte recruitment inhibitor selected fromcompounds of formulae (I) and (II), enantiomers, diastereomers,racemates, tautomers, hydrates, solvates thereof, pharmaceuticallyacceptable salts, amides and esters thereof.

DETAILED DESCRIPTION

The present invention is directed to compounds of formulae (I) or (II)as herein defined, enantiomers, diastereomers, racemates, tautomers,hydrates, solvates thereof, pharmaceutically acceptable salts, amidesand esters thereof, pharmaceutical compositions that contain at leastone of such compounds, methods of using, including treatment and/orprevention of conditions such as those that are mediated by the H₄receptor, and methods of making such pharmaceutical compositions.

The following terms are defined below, and by their usage throughout thedisclosure.

“Alkyl” includes straight chain and branched hydrocarbons with at leastone hydrogen removed to form a radical group. Alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, andso on. Alkyl does not include cycloalkyl.

“Alkenyl” includes straight chain and branched hydrocarbon radicals asabove with at least one carbon-carbon double bond (sp²). Unlessindicated otherwise by the prefix that indicates the number of carbonmembers, alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl(or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl,butadienyls, pentenyls, hexa-2,4-dienyl, and so on.

“Alkynyl” includes straight chain and branched hydrocarbon radicals asabove with at least one carbon-carbon triple bond (sp). Unless indicatedotherwise by the prefix that indicates the number of carbon members,alkynyls include ethynyl, propynyls, butynyls, and pentynyls.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein.

“Alkoxy” includes a straight chain or branched alkyl group with aterminal oxygen linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and so on. “Aminoalkyl”, “thioalkyl”, and “sulfonylalkyl” areanalogous to alkoxy, replacing the terminal oxygen atom of alkoxy with,respectively, NH (or NR), S, and SO₂.

Unless indicated otherwise by the prefix that indicates the number ofcarbon members, “cycloalkyl” includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and so on.

Unless indicated otherwise by the prefix that indicates the number ofmembers in the cyclic structure, “heterocyclyl”, “heterocyclic” or“heterocycle” is a 3- to 8-member aromatic, saturated, or partiallysaturated single or fused ring system that comprises carbon atomswherein the heteroatoms are selected from N, O, and S. Examples ofheterocyclyls include thiazolyl, furyl, pyranyl, isobenzofuranyl,pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl,indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl,piperazinyl, indolinyl, and morpholinyl. For example, preferredheterocyclyls or heterocyclic radicals include morpholinyl, piperazinyl,pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino, and morepreferably, piperidyl.

Carbocycle is a cycloalkyl or a partially saturated cycloalkyl that isnot benzo

“Aryl” includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, and soon, any of which may be optionally substituted. Aryl also includesarylalkyl groups such as benzyl, phenethyl, and phenylpropyl. Arylincludes a ring system containing an optionally substituted 6-memberedcarbocyclic aromatic ring, said system may be bicyclic, bridged, and/orfused. The system may include rings that are aromatic, or partially orcompletely saturated. Examples of ring systems include indenyl,pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl,benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on. Unlessindicated otherwise, the terms “heteroaryl” or “heteroaromatic” refer tothose heterocycles that are aromatic in nature. Examples illustratingheteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl,thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, pyridyl, and pyrimidinyl.

“Halo” includes fluoro, chloro, bromo, and iodo, and is preferablyfluoro or chloro.

When not specifically qualified, the terms “optionally substituted” usedherein refer to at least one valence allowed substitution, wherein thesubstituent(s) is(are) independently selected from the group comprisingat least: —C₁₋₆alkyl, halo, —CF₃, —OCF₃, —OR^(c), —SR^(c), —S(O)R^(c),—SO₂R^(c), C₁₋₄alkoxy, cyano, nitro, —C(O)NR^(a)R^(b), —C(O)phenyl,—C(O)C₁₋₆alkyl, —S(O)C₁₋₄alkyl, and —SO₂C₁₋₄alkyl.

As in standard chemical nomenclature, the group phenyl is hereinreferred to as “phenyl” or as “Ph”.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum mass of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

It is understood that substitutions and combinations of substitutionsrecited herein, whether stated explicitly or not, refer to substitutionsthat are consistent with the valency of the member being substituted.Terms such as “valence allowed site,” “valence allowed member,” andmorphological variations thereof are used in this sense. For example,“valence allowed” when applied to a carbon member refers to thetetravalency of C; it refers to the trivalency of N when applied to anitrogen member; and it refers to the bonding of a nitrogen member thatis conventionally characterized with a positive electric charge or thatis in a quaternary form. The present invention also encompassescompounds as described herein and equivalents thereof with at least onevalence allowed nitrogen member, including but not limited to aquaternary nitrogen member and a nitrogen oxide, each of which may beprepared according to known methods (See, J. March, Advanced OrganicChemistry, 4th ed., 1991, pp. 411-412, 1200-1201; R. C. Larock,Comprehensive Organic Transformations, 1989, pp. 397-400, 421-425; andreferences cited therein).

Particular preferred compounds of the invention comprise an imidazolecompound of formula (I) or (II), or an enantiomer, diastereomer,racemate, tautomer, hydrate, solvate thereof, or a pharmaceuticallyacceptable salt, amide or ester thereof, wherein R¹⁻¹², X, Y, Z, W, andn have any of the meanings defined hereinabove and equivalents thereof,or at least one of the following assignments and equivalents thereof.Such assignments may be used where appropriate with any of thedefinitions, claims or embodiments defined herein:

Y is CR¹⁰R¹¹;

Y is CH₂;

Z is N or CH;

n=1 or 2;

n=1;

one or both of R¹ and R² are a mono- or di-substituted phenyl ring;

only one of R¹ or R² is a mono-substituted phenyl ring;

R³ is —H, —F, —Cl, methyl, or ethyl;

R³ is —F, —Cl, or methyl;

R³ is —Cl or methyl;

R⁴ is —H, —F, —Cl, or methyl;

R⁵ is —H, methyl, or hydroxy;

R⁵ is H;

R⁶ and R⁷ are, independently, selected from the group consisting of

a) H,

b) methyl, ethyl, propyl, isopropyl, and

c) trifluoromethyl;

R⁶ and R⁷ are, independently, —H or methyl;

R⁸ is —H, methyl, or ethyl;

R⁸ is methyl; and

R⁹ is —H, —F, —Cl, or methyl.

Compounds of formula (I) or (II) comprise compounds that satisfy any oneof the combinations of definitions given herein and equivalents thereof.

It is understood that some compounds referred to herein are chiraland/or have geometric isomeric centers, for example E- and Z-isomers.The present invention encompasses all such optical isomers, includingdiastereoisomers and racemic mixtures, and geometric isomers thatpossess the activity that characterizes the compounds of this invention.In addition, certain compounds referred to herein can exist in solvatedas well as unsolvated forms. It is understood that this inventionencompasses all such solvated and unsolvated forms that possess theactivity that characterizes the compounds of this invention. Compoundsaccording to the present invention that have been modified to bedetectable by some analytic technique are also within the scope of thisinvention. An example of such compounds is an isotopically labeledcompound, such as an ¹⁸F isotopically labeled compound that may be usedas a probe in detection and/or imaging techniques, such as positronemission tomography (PET) and single-photon emission computed tomography(SPECT). Another example of such compounds is an isotopically labeledcompound, such as a deuterium and/or tritium labeled compound that maybe used in reaction kinetic studies.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound that may not be specificallydisclosed, but that converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Reference to a compound herein stands for a reference to any one of: (a)the actually recited form of such compound, and (b) any of the forms ofsuch compound in the medium in which the compound is being consideredwhen named. For example, reference herein to a compound such as R—COOH,encompasses reference to any one of, for example, R—COOH_((s)),R—COOH_((sol)), and R—COO⁻ _((sol)). In this example, R—COOH_((s))refers to the solid compound, as it could be for example in a tablet orsome other solid pharmaceutical composition or preparation;R—COOH_((sol)) refers to the undissociated form of the compound in asolvent, such as water; and R—COO⁻ _((sol)) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO⁻ upon dissociation in the medium being considered. Inanother example, an expression such as “exposing an entity to compoundof formula R—COOH” refers to the exposure of such entity to the form, orforms, of the compound R—COOH that exists, or exist, in the medium inwhich such exposure takes place. In this regard, if such entity is forexample in an aqueous environment, it is understood that the compoundR—COOH is in such same medium, and therefore the entity is being exposedto species such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where thesubscript “(aq)” stands for “aqueous” according to its conventionalmeaning in chemistry and biochemistry. A carboxylic acid functionalgroup has been chosen in these nomenclature examples; this choice is notintended, however, as a limitation but it is merely an illustration. Itis understood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation. No further examples in this regard are provided hereinbecause these interactions and transformations in a given medium areknown by any one of ordinary skill in the art.

Embodiments of this invention were made according to the syntheticmethods outlined in Schemes 1 and 2 and are selected from:

EX Compound 11-(3-{4-[4,5-Bis-(4-bromo-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine; 21-{3-[3-Chloro-4-(4,5-diphenyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine; 31-(3-{4-[4,5-Bis-(2-chloro-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine; 41-(3-{4-[4,5-Bis-(4-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine; 51-{3-[3-Chloro-4-(4,5-di-p-tolyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine; 61-(3-{4-[4,5-Bis-(4-fluoro-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine; 71-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine; 81-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-2-fluoro-phenoxy}-propyl)-4-methyl-piperazine; 91-(3-{4-[4,5-Bis-(4-bromo-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-[1,4]diazepane; 101-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-[1,4]diazepane 111-{3-[2-Chloro-4-(5-methyl-4-phenyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-[1,4]diazepane; 122-{3-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,5,6,7-tetrahydro-1H-benzoimidazole; 132-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,5,6,7-tetrahydro-1H-benzoimidazole; 141-Methyl-4-{3-[3-methyl-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperidine; 154-{3-[3-Chloro-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methyl-piperidine; 164-(3-{3-Chloro-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine; 174-(3-{3-Chloro-4-[4-(3,5-dichloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine; 184-(3-{4-[4-(3,5-Dichloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-propyl)-1-methyl-piperidine; 194-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine; 204-(3-{4-[4,5-Bis-(4-fluoro-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-1-methyl-piperidine; 214-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-1-methyl-piperidine; 224-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-p-tolyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine; 232-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,5,6,7-tetrahydro-1H-benzoimidazole; 244-{3-[3-Chloro-4-(4-methyl-5-propyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methyl-piperidine; 254-{3-[3-Chloro-4-(5-ethyl-4-methyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methylpiperidine; 261-Methyl-4-(2-{3-methyl-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-ethoxy)-piperidine; 275-[4-(3,5-Dichloro-phenyl)-5-methyl-1H-imidazol-2-yl]-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine; 285-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine; 292-[3-(1-Methyl-piperidin-4-yl)-propoxy]-5-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine; 302-[3-(1-Methyl-piperidin-4-yl)-propoxy]-5-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine; 312-[3-(1-Methyl-piperidin-4-yl)-propoxy]-5-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridine; 321-Methyl-4-(3-{5-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxy}-propyl)-piperazine; 331-Methyl-4-(3-{5-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxy}-propyl)-piperazine; 344-(4-{3-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-butyl)-1-methyl-piperidine; 351-Methyl-4-{4-[3-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-butyl}-piperidine; 362-[4-(1-Methyl-piperidin-4-yl)-butoxy]-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridine; 372-[4-(1-Methyl-piperidin-4-yl)-butoxy]-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine; 384-{3-[4-(5-Isobutyl-4-methyl-1H-imidazol-2-yl)-3-methyl-phenoxy]-propyl}-1-methyl-piperidine; 394-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine; 404-{3-[3-Chloro-4-(5-isobutyl-4-methyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methyl-piperidine; 411-Methyl-4-(4-{3-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-butyl)-piperidine; 421-{3-[2-Chloro-4-(1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine; 431-{3-[3-Chloro-4-(4,5-dimethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine; 441-{3-[3-Chloro-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine; 451-{3-[2-Chloro-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-[1,4]diazepane; 461-Methyl-4-(3-{3-methyl-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-propyl)-piperidine; 474-(3-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-propyl)-1-methyl-piperidine; 484-(2-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-ethoxy)-1-methyl-piperidine; 491-(3-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-2-methyl-propyl)-4-methyl-piperazine; 502-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-6-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine; 514-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-5-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine; 525-Bromo-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine; 532,4-Dimethyl-1-{3-[4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperazine; 541,2-Dimethyl-4-{3-[4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperazine; 553-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridine; 561-Methyl-4-(4-{4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxy}-butyl)-[1,4]diazepane; 575-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine; 584-[4-(4-Chloro-phenyl)-5-trifluoromethyl-1H-imidazol-2-yl]-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyrimidine; 594-(3-{4-[5-Cyclopropylmethyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-3-methyl-phenoxy}-propyl)-1-methyl-piperidine; 601-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-3-(4-methyl-piperazin-1-yl)-propan-2-ol; 614-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-piperidine; 624-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-ethyl-piperidine; 634-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-isopropyl-piperidine; 641-Methyl-4-{3-[4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-naphthalen-1-yloxy]-propyl}-piperidine; 651-(4-Methyl-piperazin-1-yl)-3-{5-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxy}-propan-1-one; 666-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-fluoro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine; 671-Methyl-4-(4-{3-methyl-6-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxy}-butyl)-piperazine; 681-Methyl-4-{3-[4-(5-methyl-4-thiophen-2-yl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperidine; and 692-{3-[4-(1-Methyl-piperidin-4-yl)-butoxy]-phenyl}-3H-imidazo[4,5-b]pyridine.

Compounds according to the present invention may be made according toprocesses within the skill of the art and/or according to processes ofthis invention, such as those described in the schemes and examples thatfollow and by matrix or combinatorial methods. To obtain the variouscompounds herein, starting materials may be employed that carry theultimately desired substituents though the reaction scheme with orwithout protection as appropriate. Starting materials may be obtainedfrom commercial sources or synthesized by methods known to one skilledin the art. Alternatively, it may be necessary to employ, in the placeof the ultimately desired substituent, a suitable group, which may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Those of ordinary skill in the art will be able tomodify and adapt the guidance provided herein to make compoundsaccording to the present invention.

Embodiments of processes illustrated herein include, when chemicallymeaningful, one or more steps such as hydrolysis, halogenation,protection, and deprotection. These steps can be implemented in light ofthe teachings provided herein and the ordinary skill in the art.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. Inaddition, compounds of this invention may be modified by usingprotecting groups; such compounds, precursors, or prodrugs are alsowithin the scope of the invention. This modification may be achieved bymeans of conventional protecting groups, such as those described in“Protective Groups in Organic Chemistry”, ed. J. F. W. McOmie, PlenumPress, 1973; and T. W. Greene & P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, 3^(rd) ed., John Wiley & Sons, 1999. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Table of Acronyms Term Acronym Tetrahydrofuran THF N,N-DimethylformamideDMF N,N-Dimethylacetamide DMA Dimethyl sulfoxide DMSOtert-Butylcarbamoyl BOC Bovine serum albumin BSA High-pressure liquidchromatography HPLC Thin layer chromatography TLC Diisobutylaluminumhydride DIBAL-H Ethyl acetate EtOAc Acetate OAc

Referring to Schemes 1 and 2, there are disclosed the following notesand additions. The starting materials for the steps described belowregarding Schemes 1 and 2 are commercially available or easilyaccessible to those skilled in the art.

Compounds of formula (I) or (II) are prepared by condensing a suitablysubstituted 1,2-diketone (III) with a suitably substituted aldehyde(IV′) or (IV″) in the presence of a source of ammonia (NH₃) to form acompound of formula (I) when the aldehyde (IV′) has a para ethersubstitution with respect to the aldehyde group (Scheme 1), or acompound of formula (II) when the aldehyde (IV″) has a meta ethersubstitution with respect to the aldehyde group (Scheme 2). Suitablesources of ammonia include liquid and gaseous ammonia, aqueous ammonia,ammonia in methyl or ethyl alcohol, ammonia in 1,4-dioxane, NH₄OAc,NH₄C₁, NH₄HCO₃, (NH₄)₂CO₃, ammonium benzoate, and other chemicallycompatible sources of ammonia or ammonium salts, and mixtures thereof.

This condensation is preferably performed in a heated medium in achemically compatible solvent. Reaction medium temperatures rangepreferably from about room temperature to about 110° C., more preferablyfrom about 50° C. to about 80° C. Solvents that can be used for thisreaction include ethanol, isopropanol, acetic acid, water, THF, dioxane,DMF, DMA, and DMSO, preferably methanol, and mixtures thereof.

Suitably substituted aryl or heteroaryl aldehydes (IV′) and (IV″) can beprepared according to procedures known in the art. In one preparationprocedure, a suitably substituted hydroxy benzaldehyde is reacted with asuitably substituted moiety to form the ether link in compounds (IV′)and (IV″). Reaction with a suitably substituted 4-hydroxy benzaldehydeleads to the formation of compound (IV′), and reaction with a suitablysubstituted 3-hydroxy benzaldehyde leads to the formation of compound(IV″).

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as resolution, for exampleby formation of diastereomeric salts, kinetic resolution includingvariants thereof, such as dynamic resolution, preferentialcrystallization, biotransformation, enzymatic transformation, andpreparative chromatography. The compounds may be prepared in racemicform, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The compounds may, forexample, be resolved into their component enantiomers by standardtechniques, such as the formation of diastereomeric pairs by saltformation with an optically active acid, such as(−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acidfollowed by fractional crystallization and regeneration of the freebase. The compounds may also be resolved by formation of diastereomericesters or amides, followed by chromatographic separation and removal ofthe chiral auxiliary. Alternatively, the compounds may be separatedusing a chiral HPLC column. Regioisomeric mixtures may also be separatedinto their constituent regioisomers by conventional techniques.

For therapeutic use, salts of the compounds of the present invention arethose that are pharmaceutically acceptable. However, salts of acids andbases that are non-pharmaceutically acceptable may also find use, forexample, in the preparation or purification of a pharmaceuticallyacceptable compound. All salts, whether pharmaceutically acceptable ornot are included within the ambit of the present invention.

Pharmaceutically acceptable salts, esters, and amides of compoundsaccording to the present invention refer to those salts, amides andester forms of the compounds of the present invention that would beapparent to the pharmaceutical chemist, i.e., those that are non-toxicand that would favorably affect the pharmacological properties of saidcompounds of the present invention. Those compounds having favorablepharmacological properties would be apparent to the pharmaceuticalchemist, i.e., those that are non-toxic and that possess suchpharmacological properties to provide sufficient palatability,absorption, distribution, metabolism and excretion. Other factors, morepractical in nature, that are also important in the selection are costof raw materials, ease of crystallization, yield, stability,hygroscopicity, and flowability of the resulting bulk drug.

Examples of acids that may be used in the preparation ofpharmaceutically acceptable salts include the following: acetic acid,2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginicacid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoicacid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid,(−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonicacid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid,phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid,4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid and undecylenic acid.

Compounds of the present invention containing acidic protons may beconverted into their therapeutically active non-toxic metal or amineaddition salt forms by treatment with appropriate organic and inorganicbases. Appropriate base salt forms comprise, for example, the ammoniumsalts; the alkali and earth alkaline metal salts (e.g. lithium, sodium,potassium, magnesium, calcium salts, which may be prepared by treatmentwith, for example, magnesium hydroxide, calcium hydroxide, potassiumhydroxide, zinc hydroxide, or sodium hydroxide); and amine salts madewith organic bases (e.g. primary, secondary and tertiary aliphatic andaromatic amines such as L-arginine, benethamine, benzathine, choline,deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine,diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine,ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,methylamine, piperidine, piperazine, propylamine, pyrrolidine,1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,isoquinoline, secondary amines, triethanolamine, trimethylamine,triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine). See, e.g.,S. M. Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977,66:1-19, which is incorporated herein by reference.

“Salt” also comprises the hydrates and solvent addition forms thatcompounds of the present invention are able to form. Examples of suchforms are hydrates, alcoholates, and generally solvates.

Examples of suitable esters include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl,substituted phenyl, and phenylC₁₋₆alkyl-esters. Preferred esters includemethyl esters. Furthermore, examples of suitable esters include suchesters where one or more carboxyl substituents is replaced withp-methoxybenzyloxy-carbonyl, 2,4,6-trimethylbenzyloxycarbonyl,9-anthryloxycarbonyl, CH₃SCH₂COO—, tetrahydrofur-2-yloxycarbonyl,tetrahydropyran-2-yloxy-carbonyl, fur-2-yloxycarbonyl,benzoylmethoxycarbonyl, p-nitrobenzyloxy-carbonyl,4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, t-butyloxycarbonyl, t-amyloxycarbonyl,diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, adamantyloxycarbonyl,2-benzyloxyphenyloxycarbonyl, 4-methylthiophenyloxycarbonyl, ortetrahydropyran-2-yloxycarbonyl.

Whether referred to herein explicitly or not, each of the terms“pharmaceutically acceptable salts,” “pharmaceutically acceptableesters,” and “pharmaceutically acceptable amides” include those salts,esters and amides, respectively that do not change the intrinsicproperties of the active ingredient. See, for example, Remington, TheScience and Practice of Pharmacy, 704 (20^(th) ed., 2000).

“Patient” or “subject” includes mammals such as human beings and animals(e.g., dogs, cats, horses, rats, rabbits, mice, non-human primates) inneed of observation, experiment, treatment or prevention in connectionwith the relevant disease or condition. Preferably, the patient is ahuman being.

“Composition” includes a product comprising the specified ingredients inthe specified amounts, including in the effective amounts, as well asany product that results directly or indirectly from combinations of thespecified ingredients in the specified amounts.

Administration of at least one compound of formulae (I) and (II) and/orderivative thereof refers to the administration of such compound in asuitable administration form, whether as such compound itself or as partof a suitable pharmaceutical composition.

“Therapeutically effective amount” or “effective amount” andgrammatically related terms mean that amount of active compound orpharmaceutical agent that elicits the biological or medicinal responsein an in vitro system, a tissue system, an animal or human being, thatis being sought by a researcher, veterinarian, medical doctor, or otherclinician, where the medicinal response includes, but is not limited to,alleviation of the symptoms of the disease or disorder being treated.Analogously, terms such as “inhibitory amount”, “anti-inflammatoryamount,” “prophylactically effective amount” and grammatically relatedterms refer to the amount of active compound or pharmaceutical agentthat elicits the response being referred to, such as inhibition andanti-inflammatory effect, respectively, in the system being studied,whether an in vitro system, an animal or a human being that is sought bya researcher, veterinarian, medical doctor, or other clinician, wherethe medicinal response includes, but is not limited to, alleviation ofthe symptoms of the disease or disorder being treated.

As used herein, “treating” a disorder, and grammatically related terms,mean eliminating or otherwise ameliorating the cause and/or effectsthereof. Terms such as to “inhibit”, and grammatically related terms,the onset of a disorder or event, and to “prevent” a disorder orcondition, and grammatically related terms, mean preventing, delaying orreducing the likelihood of such onset.

The terms “unit dose” and their grammatical equivalent forms are usedherein to refer to physically discrete units suitable as unitary dosagesfor human patients and other animals, each unit containing apredetermined effective, pharmacologic amount of the active ingredientcalculated to produce the desired pharmacological effect. Thespecifications for the novel unit dosage forms of this invention aredetermined by, and are directly dependent on, the characteristics of theactive ingredient, and on the limitations inherent in the art ofcompounding such an active ingredient for therapeutic use in humans andother animals.

Embodiments of pharmaceutical compositions for treating or preventing anH₄ receptor-mediated condition in a subject that comprise atherapeutically effective amount of at least one H₄ receptor modulatorselected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates, tautomers, hydrates, solvates thereof,pharmaceutically acceptable salts, amides and esters thereof, furthercomprise a pharmaceutically acceptable carrier.

Embodiments of pharmaceutical compositions for inhibiting leukocyterecruitment in a subject that comprise a therapeutically effectiveamount of at least one leukocyte recruitment inhibitor selected fromcompounds of formulae (I) and (II), enantiomers, diastereomers,racemates, tautomers, hydrates, solvates thereof, pharmaceuticallyacceptable salts, amides and esters thereof, further comprise apharmaceutically acceptable carrier.

Embodiments of anti-inflammatory compositions that comprise atherapeutically effective amount of at least one anti-inflammatorycompound selected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates, tautomers, hydrates, solvates thereof,pharmaceutically acceptable salts, amides and esters thereof, furthercomprise a pharmaceutically acceptable carrier.

Embodiments of methods for treating or preventing inflammation in asubject that comprise administering to the subject in connection with aninflammatory response a pharmaceutical composition comprising atherapeutically effective amount of at least one anti-inflammatorycompound selected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates, tautomers, hydrates, solvates thereof,pharmaceutically acceptable salts, amides and esters thereof, includemethods wherein said inflammatory response is a response to at least oneof the conditions: inflammatory disorders, allergic disorders,dermatological disorders, autoimmune disease, lymphatic disorders, itchyskin, and immunodeficiency disorders.

Embodiments of methods for treating or preventing inflammation in asubject that comprise administering to the subject in connection with aninflammatory response a pharmaceutical composition comprising atherapeutically effective amount of at least one anti-inflammatorycompound selected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates, tautomers, hydrates, solvates thereof,pharmaceutically acceptable salts, amides and esters thereof, includemethods wherein said inflammatory response is a response tochemotherapy.

Embodiments of methods for treating or preventing inflammation in asubject that comprise administering to the subject in connection with aninflammatory response a pharmaceutical composition comprising atherapeutically effective amount of at least one anti-inflammatorycompound selected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates, tautomers, hydrates, solvates thereof,pharmaceutically acceptable salts, amides and esters thereof, includemethods wherein at least one of the following is satisfied: saidinflammatory response is a response to a physical stimulus; saidinflammatory response is a response to a chemical stimulus; saidinflammatory response is a response to infection; said inflammatoryresponse is a response to an invasion by a body that is foreign to saidsubject; said inflammatory response is a response to an immunologicalstimulus; said inflammatory response is a response to anon-immunological stimulus; said inflammatory response is a response toat least one of the conditions: Allergy, asthma, chronic obstructedpulmonary disease (COPD), atherosclerosis, rheumatoid arthritis,multiple sclerosis, inflammatory bowel disease, and more specificallywherein said inflammatory bowel disease is at least one of Crohn'sdisease and ulcerative colitis, psoriasis, allergic rhinitis,scleroderma, autoimmune thyroid disease, immune-mediated diabetesmellitus, and lupus; said inflammatory response is a response to atleast one of the conditions: Myasthenia gravis, autoimmune neuropathy,and more specifically wherein said autoimmune neuropathy isGuillain-Barré neuropathy, autoimmune uveitis, autoimmune hemolyticanemia, pernicious anemia, autoimmune thrombocytopenia, temporalarteritis, anti-phospholipid syndrome, vasculitides, and morespecifically wherein said vasculitides is Wegener's granulomatosis,Behcet's disease, dermatitis herpetiformis, pemphigus vulgaris,vitiligio, primary biliary cirrhosis, autoimmune hepatitis, autoimmuneoophoritis, autoimmune orchitis, autoimmune disease of the adrenalgland, polymyositis, dermatomyositis, spondyloarthropathy, and morespecifically wherein said spondyloarthropathy is ankylosing spondylitis,and Sjogren's syndrome; said inflammatory response is acuteinflammation; said inflammatory response is allergic inflammation; andsaid inflammatory response is chronic inflammation. Administration inconnection with an inflammatory response according to the presentinvention includes administration at a time that is at least one ofprior to, at the onset of, and after inflammation is detected.

Embodiments of methods for modulating an H₄ receptor expression thatcomprise exposing an H₄ receptor to at least one compound selected fromcompounds of formulae (I) and (II), enantiomers, diastereomers,racemates, tautomers, hydrates, solvates thereof, pharmaceuticallyacceptable salts, amides and esters thereof, include methods wherein atleast one of the following is satisfied: said at least one compoundmodulates the H₄ receptor expression as a receptor antagonist, and saidat least one compound of modulates the H₄ receptor expression as areceptor partial agonist.

An illustration of the invention is a pharmaceutical composition made bymixing at least one imidazole compound selected from compounds offormulae (I) and (II), enantiomers, diastereomers, racemates, tautomers,hydrates, solvates thereof, pharmaceutically acceptable salts, amidesand esters thereof, and a pharmaceutically acceptable carrier.Illustrating the invention is a process for making a pharmaceuticalcomposition comprising mixing at least one imidazole compound selectedfrom compounds of formulae (I) and (II), enantiomers, diastereomers,racemates, tautomers, hydrates, solvates thereof, pharmaceuticallyacceptable salts, amides and esters thereof, and a pharmaceuticallyacceptable carrier.

Another example of the invention is the use of a composition thatcomprises at least one imidazole compound selected from compounds offormulae (I) and (II), enantiomers, diastereomers, racemates, tautomers,hydrates, solvates thereof, pharmaceutically acceptable salts, amidesand esters thereof, in the preparation of a medication for treating anyone of the conditions referred to herein; one of such conditions isinflammation. Another example of the invention is the use of acomposition that comprises at least one imidazole compound selected fromcompounds of formulae (I) and (II), enantiomers, diastereomers,racemates, tautomers, hydrates, solvates thereof, pharmaceuticallyacceptable salts, amides and esters thereof, in the treatment orprevention of any one of the conditions referred to herein; one of suchconditions is inflammation.

The expression of the H₄ receptor in immune cells, including someleukocytes and mast cells, establishes it as an important target fortherapeutic intervention in a range of immunological and inflammatorydisorders (such as allergic, chronic, or acute inflammation).Specifically H₄ receptor ligands are expected to be useful for thetreatment or prevention of various mammalian disease states.

Thus, according to the invention, the disclosed compounds, whetherpartial agonists or antagonists of the H₄ receptor, and compositions areuseful for the amelioration of symptoms associated with, the treatmentof, and the prevention of, the following conditions and diseases:inflammatory disorders, allergic disorders, dermatological disorders,autoimmune disease, lymphatic disorders, and immunodeficiency disorders,including the more specific conditions and diseases given above. Thedisclosed compounds may also be useful as adjuvants in chemotherapy orin the treatment of itchy skin.

Aspects of the invention include (a) a pharmaceutical compositioncomprising an imidazole compound selected from compounds of formulae (I)and (II), enantiomers, diastereomers, racemates, tautomers, hydrates,solvates thereof, pharmaceutically acceptable salts, amides and estersthereof, and a preferred compound as described herein, and apharmaceutically acceptable carrier; (b) a packaged drug comprising (1)a pharmaceutical composition comprising at least one imidazole compoundselected from compounds of formulae (I) and (II), enantiomers,diastereomers, racemates, tautomers, hydrates, solvates thereof,pharmaceutically acceptable salts, amides and esters thereof, or one ormore preferred compounds as described herein, and a pharmaceuticallyacceptable carrier, and (2) instructions for the administration of saidcomposition for the treatment or prevention of an H₄-mediated disease orcondition.

Embodiments of this invention provide methods for treating anH₄-mediated condition in a patient, said methods comprisingadministering to the patient a pharmaceutically effective amount of acomposition comprising at least one imidazole compound selected fromcompounds of formulae (I) and (II), enantiomers, diastereomers,racemates, tautomers, hydrates, solvates thereof, pharmaceuticallyacceptable salts, amides and esters thereof, and other disclosed orpreferred compounds. In these conditions, the action of the H₄ receptoris involved. For example, the invention features a method for treatingan H₄ mediated condition in a patient, said method comprisingadministering to the patient a pharmaceutically effectiveH₄-antagonizing amount of a composition comprising at least oneimidazole compound selected from compounds of formulae (I) and (II),enantiomers, diastereomers, racemates, tautomers, hydrates, solvatesthereof, pharmaceutically acceptable salts, amides and esters thereof.

The effect of an antagonist may also be produced by an inverse agonist.Inverse agonism describes the property of a compound to actively turnoff a receptor that displays constitutive activity. Constitutiveactivity can be identified in cells that have been forced toover-express the human H₄ receptor. Constitutive activity can bemeasured by examining cAMP levels or by measuring a reporter genesensitive to cAMP levels after a treatment with a cAMP-stimulating agentsuch as forskolin. Cells that over-express H₄ receptors will displaylower cAMP levels after forskolin treatment than non-expressing cells.Compounds that behave as H₄ agonists will dose-dependently lowerforskolin-stimulated cAMP levels in H₄-expressing cells. Compounds thatbehave as H₄ inverse agonists will dose-dependently stimulate cAMPlevels in H₄-expressing cells. Compounds that behave as H₄ antagonistswill block either H₄ agonist-induced inhibition of cAMP or H₄ inverseagonist-induced increases in cAMP.

Further embodiments of the invention include disclosed compounds thatare inhibitors of a mammalian histamine H₄ receptor function, inhibitorsof inflammation or inflammatory responses in vivo or in vitro,modulators of the expression of a mammalian histamine H₄ receptorprotein, inhibitors of polymorphonuclear leukocyte activation in vivo orin vitro, or combinations of the above, and corresponding methods oftreatment, prophylaxis, and diagnosis comprising the use of a disclosedcompound.

The pharmaceutical compositions can be prepared using conventionalpharmaceutical excipients and compounding techniques. Examples ofsuitable unit dosage forms are tablets, capsules, pills, powders, powderpackets, granules, wafers, and the like, segregated multiples of anyunit dosage form, as well as liquid solutions, and suspensions. Someliquid forms are aqueous, whereas other embodiments of liquid forms arenon-aqueous. Oral dosage forms may be elixirs, syrups, capsules, tabletsand the like. Examples of solid carriers include those materials usuallyemployed in the manufacture of pills or tablets, such as lactose,starch, glucose, methylcellulose, magnesium stearate, dicalciumphosphate, mannitol and the like, thickeners such as tragacanth andmethylcellulose USP, finely divided SiO₂, polyvinylpyrrolidone,magnesium stearate, and the like. Typical liquid oral excipients includeethanol, glycerol, water and the like. All excipients may be mixed asneeded with diluents (for example, sodium and calcium carbonates, sodiumand calcium phosphates, and lactose), disintegrants (for example,cornstarch and alginic acid), granulating agents, lubricants (forexample, magnesium stearate, stearic acid, and talc), binders (forexample, starch and gelatin), thickeners (for example, paraffin, waxes,and petrolatum), flavoring agents, coloring agents, preservatives, andthe like by conventional techniques known to those of ordinary skill inthe art of preparing dosage forms. Coatings can be present and include,for example, glyceryl monostearate and/or glyceryl diestearate. Capsulesfor oral use include hard gelatin capsules in which the activeingredient is mixed with a solid diluent, and soft gelatin capsules, inwhich the active ingredient is mixed with water or an oil, such aspeanut oil, liquid paraffin, or olive oil.

Parenteral dosage forms may be prepared using water or another sterilecarrier. Parenteral solutions can be packaged in containers adapted forsubdivision into individual doses. For intramuscular, intraperitoneal,subcutaneous, and intravenous use, the compounds of the invention willgenerally be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity. Suitable aqueous vehiclesinclude Ringer's solution and isotonic sodium chloride. Aqueoussuspensions may include suspending agents such as cellulose derivatives,sodium alginate, polyvinyl-pyrrolidone, and gum tragacanth, and awetting agent, such as lecithin. Suitable preservatives for aqueoussuspensions include ethyl and n-propyl p-hydroxybenzoate. Parenteralformulations include pharmaceutically acceptable aqueous or non-aqueoussolutions, dispersion, suspensions, emulsions, and sterile powders forthe preparation thereof. Examples of carriers include water, ethanol,polyols (propylene glycol, polyethylene glycol), vegetable oils, andinjectable organic esters such as ethyl oleate. Fluidity can bemaintained by the use of a coating such as lecithin, a surfactant, ormaintaining appropriate particle size. Carriers for solid dosage formsinclude (a) fillers or extenders, (b) binders, (c) humectants, (d)disintegrating agents, (e) solution retarders, (f) absorptionaccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and(j) propellants.

To aid solubility, suitable ingredients, such as cyclodextrins, may beincluded in the compositions. Appropriate cyclodextrins (CD) are α-, β-,γ-cyclodextrins or ethers and mixed ethers thereof wherein one or moreof the hydroxy groups of the anhydroglucose units of the cyclodextrinare substituted with C₁₋₆alkyl, particularly methyl, ethyl or isopropyl,for example randomly methylated β-CD; hydroxyC₁₋₆alkyl, particularlyhydroxyethyl, hydroxy-propyl or hydroxybutyl; carboxyC₁₋₆alkyl,particularly carboxymethyl or carboxy-ethyl; C₁₋₆alkylcarbonyl,particularly acetyl. Especially noteworthy as complexants and/orsolubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl-β-CD,2-hydroxyethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD). The term mixed ether denotes cyclodextrin derivativeswherein at least two cyclodextrin hydroxy groups are etherified withdifferent groups such as, for example, hydroxy-propyl and hydroxyethyl.

Compositions may also contain adjuvants such as preserving, wetting,emulsifying, and dispensing agents; antimicrobial agents such asparabens, chlorobutanol, phenol, and sorbic acid; isotonic agents suchas a sugar or sodium chloride; absorption-prolonging agents such asaluminum monostearate and gelatin; and absorption-enhancing agents.

Physiologically acceptable carriers are well known in the art. Examplesof liquid carriers are solutions in which compounds according to thepresent invention form solutions, emulsions, and dispersions. Compatibleantioxidants, such as methylparaben and propylparaben, can be present insolid and/or liquid compositions, as can sweeteners.

Pharmaceutical compositions according to the present invention mayinclude suitable emulsifiers typically used in emulsion compositions.Such emulsifiers are described in standard publications such as H. P.Fiedler, 1989, Lexikon der Hilfsstoffe für Pharmazie, Kosmetic andagrenzende Gebiete, Cantor ed., Aulendorf, Germany, and in Handbook ofPharmaceutical Excipients, 1986, American Pharmaceutical Association,Washington, D.C., and the Pharmaceutical Society of Great Britain,London, UK, which are incorporated herein by reference. Gelling agentsmay also be added to compositions according to this invention.Polyacrylic acid derivatives, such as carbomers, are examples of gellingagents, and more particularly, various types of carbopol, which aretypically used in amounts from about 0.2% to about 2%. Suspensions maybe prepared as a cream, an ointment, including a water-free ointment, awater-in-oil emulsion, an oil-in-water emulsion, an emulsion gel, or agel.

It is anticipated that the compounds of the invention can beadministered by oral or parenteral routes, including intravenous,intramuscular, intraperitoneal, subcutaneous, rectal, intracisternal,intravaginal, intravesical, topical or local administration, and byinhalation (buccal or nasal, preferably in the form of a spray). Fororal administration, the compounds of the invention will generally beprovided in the form of tablets, capsules, or as a solution orsuspension. Other methods of administration include controlled releaseformulations, such as subcutaneous implants and dermal patches.

Compounds according to the present invention and mixtures thereofprovide embodiments of active substance in pharmaceutical compositionsthat can be made with excipients and ingredients and with ordinary skillin the art. Lists of excipients and ingredients for pharmaceuticalcompositions are available in standard references. For example, astandard text such as The Science and Practice of Pharmacy, A. R.Gennaro, ed., provides 20 chapters in part 5, pp. 669-1050, onpharmaceutical manufacturing, including lists of ingredients tomanufacture pharmaceutical compositions such as solutions (includingaromatic waters, aqueous acids, douches, enemas, gargles, mouthwashes,juices, nasal solutions, otic solutions, irrigation solutions, syrups,honeys, mucilages, jellies, collodions, elixirs, glycerins, inhalants,liniments, oleopreparations, spirits, and drops), emulsions (includingmultiple emulsions and microemulsions), suspensions, (including gels,lotions, tablet-formulated suspensions, magmas and milks, mixtures, andofficial suspensions), extracts, parenteral preparations, intravenouspreparations, ophthalmic preparations, topical preparations, oral soliddosage forms, coatings, controlled-release drug delivery systems,aerosols, packaging materials, antioxidants, preservatives, coloringagents, flavoring agents, diluting agents, vehicles, emulsifying agents,suspending agents, ointment bases, pharmaceutical solvents, andmiscellaneous pharmaceutical necessities, including the techniques anddevices for manufacturing such preparations.

Effective doses of the compounds of the present invention may beascertained by conventional methods. The specific dosage level requiredfor any particular patient will depend on a number of factors, includingseverity of the condition, type of symptoms needing treatment, the routeof administration, the weight, age, and general condition of thepatient, and the administration of other medicaments. In general, it isanticipated that the daily dose (whether administered as a single doseor as divided doses) will be in the range from about 0.01 mg to about1000 mg per day, more usually from about 1 mg to about 500 mg per day,and most usually form about 10 mg to about 200 mg per day. Expressed asdosage per unit body weight, a typical dose will be expected to bebetween about 0.0001 mg/kg and about 15 mg/kg, especially between about0.01 mg/kg and about 7 mg/kg, and most especially between about 0.15mg/kg and 2.5 mg/kg.

Anticipated oral dose ranges include from about 0.01 to 500 mg/kg,daily, more preferably from about 0.05 to about 100 mg/kg, taken in 1-4separate doses. Some compounds of the invention may be orally dosed inthe range of about 0.05 to about 50 mg/kg daily, while others may bedosed at 0.05 to about 20 mg/kg daily. Infusion doses can range fromabout 1.0 to about 1.0×10⁴ μg/(kg·min) of inhibitor, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days. For topical administration, compounds of the presentinvention may be mixed with a pharmaceutical carrier at a concentrationfrom about 0.1 to about 10% of drug to vehicle. Capsules, tablets orother formulations (such as liquids and film-coated tablets) may be ofbetween 0.5 and 200 mg, such as 1, 3, 5, 10, 15, 25, 35, 50 mg, 60 mg,and 100 mg and can be administered according to the disclosed methods.Daily dosages are envisaged to be, for example, between 10 mg and 5000mg for an adult human being of normal weight.

EXAMPLES General Experimental Methods

Nuclear magnetic resonance (NMR) spectra were obtained on either aBruker model DPX400 (400 MHz) or DPX500 (500 MHz) spectrometer. Theformat of the ¹H NMR data below is: chemical shift in ppm down field ofthe tetramethylsilane reference (multiplicity, coupling constant J inHz, integration).

Mass spectra (MS) were obtained on a Hewlett Packard (Agilent) series1100 MSD using electrospray ionization (ESI) in either positive ornegative mode as indicated. The “mass calculated” (calcd) for amolecular formula is the monoisotopic mass of the compound.

Purification Method 1:

2-Arylimidazoles were purified by chromatography (silica gel, 0-10% (2.0M ammonia in methanol) in dichloromethane. The reaction mixtures wereloaded on silica gel without work-up.

Example 1

1-(3-{4-[4,5-Bis-(4-bromo-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine

General Procedure 1.

A. 2-Chloro-4-(3-chloro-propoxy)-benzaldehyde. 1-Bromo-3-chloropropane(2.55 g, 16.2 mmol, 1.0 equiv) was added to a solution of2-chloro-4-hydroxybenzaldehyde (2.54 g, 16.2 mmol) and K₂CO₃ (4.48 g,32.4 mmol) in acetonitrile (41 mL). The mixture was heated at 65° C. for18 h, then cooled to room temperature (rt) and filtered throughdiatomaceous earth. The filtrate was concentrated to yield the crudeproduct, which was purified by column chromatography (silica gel, 5%EtOAc in hexanes) to afford 3.19 g of a colorless oil (66%). ¹H NMR (400MHz, CD₃OD): 10.3 (s, 1H), 7.87 (d, J=8.0, 1H), 7.10 (d, J=4.0, 1H),7.03 (dd, J=8.0, 4.0, 1H), 4.23 (t, J=8.0, 2H), 3.76 (t, J=8.0, 2H),2.31-2.22 (m, 2H).General Procedure 2.B. 2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde.N-Methylpiperazine (2.16 g, 21.5 mmol),2-chloro-4-(3-chloro-propoxy)-benzaldehyde (3.19 g, 10.8 mmol), K₂CO₃(4.46 g, 32.3 mmol), and KI (1.02 g, 5.38 mmol) were stirred inn-butanol (22 mL) at 90° C. for 18 h. The reaction mixture was dilutedwith water and then extracted three times with EtOAc. The combinedextracts were dried (Na₂SO₄), filtered, and concentrated, yielding thecrude product, which was purified by Method 1 to afford 2.04 g (63%) ofan orange oil. ¹H NMR (400 MHz, CD₃OD): 10.3 (s, 1H), 7.86 (d, J=8.0,1H), 7.08 (d, J=2.0, 1H), 7.00 (dd, J=8.0, 2.0, 1H), 4.15 (t, J=8.0,2H), 3.00-2.30 (br s, 10H), 2.29 (s, 3H), 2.05-1.90 (m, 2H).General Procedure 3.C.1-(3-{4-[4,5-Bis-(4-bromo-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine.2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (37 mg,0.12 mmol) and 1,2-bis-(4-bromo-phenyl)-ethane-1,2-dione (59 mg, 0.16mmol) were stirred with NH₄OAc (28 mg, 0.37 mmol) in methanol (0.25 M)at 65° C. for 2 d. The reaction mixture was purified by Method 1 toafford 22 mg (28%) of the title compound. MS (ESI): mass calcd forC₂₉H₂₉Br₂ClN₄O, 642.04. m/z found, 645.0 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): 7.62 (d, J=8.6, 1H), 7.50 (d, J=8.0, 4H), 7.38 (d, J=7.9, 4H),7.12 (d, J=2.5, 1H), 7.00 (dd, J=8.7, 2.5, 1H), 4.10 (t, J=6.1, 2H),2.85-2.25 (m, 10H), 2.29 (s, 3H), 2.02-1.98 (m, 2H).The following compounds in Examples 2-13 were prepared using methodsanalogous to those described in Example 1 with the appropriatesubstituent changes.

Example 2

1-{3-[3-Chloro-4-(4,5-diphenyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine

MS (ESI): mass calcd for C₂₉H₃₁ClN₄O, 486.22. m/z found, 487.5 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.64 (d, J=8.6, 1H), 7.49-7.46 (m, 4H),7.35-7.25 (m, 6H), 7.12 (d, J=2.5, 1H), 7.00 (dd, J=8.7, 2.5, 1H), 4.09(t, J=6.1, 2H), 2.80-2.35 (m, 10H), 2.29 (s, 3H), 2.02-1.98 (m, 2H).

Example 3

1-(3-{4-[4,5-Bis-(2-chloro-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine

MS (ESI): mass calcd for C₂₉H₂₉Cl₃N₄O, 554.14. m/z found, 557.5 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.69 (d, J=8.7, 1H), 7.42-7.20 (m, 8H), 7.12(d, J=2.5, 1H), 7.00 (dd, J=8.7, 2.5, 1H), 4.09 (t, J=6.1, 2H),2.80-2.35 (m, 10H), 2.29 (s, 3H), 2.02-1.98 (m, 2H).

Example 4

1-(3-{4-[4,5-Bis-(4-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine

MS (ESI): mass calcd for C₃₁H₃₅ClN₄O₃, 546.24. m/z found, 547.5 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.61 (d, J=8.6, 1H), 7.38 (d, J=8.8, 4H), 7.10(d, J=2.5, 1H), 6.97 (dd, J=8.6, 2.5, 1H), 6.88 (d, J=8.8, 4H), 4.08 (t,J=6.1, 2H), 3.79 (s, 6H), 2.80-2.35 (m, 10H), 2.29 (s, 3H), 2.05-1.95(m, 2H).

Example 5

1-{3-[3-Chloro-4-(4,5-di-p-tolyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine

MS (ESI): mass calcd for C₃₁H₃₅ClN₄O, 514.25. m/z found, 515.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.62 (d, J=8.6, 1H), 7.35 (d, J=7.8, 4H), 7.13(d, J=7.9, 4H), 7.10 (d, J=2.5, 1H), 6.98 (dd, J=8.6, 2.5, 1H), 4.08 (t,J=6.1, 2H), 2.80-2.35 (m, 10H), 2.33 (s, 6H), 2.28 (s, 3H), 2.01-1.96(m, 2H).

Example 6

1-(3-{4-[4,5-Bis-(4-fluoro-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine

MS (ESI): mass calcd for C₂₉H₂₉ClF₂N₄O, 522.20. m/z found, 523.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.63 (d, J=8.6, 1H), 7.48-7.44 (m, 4H), 7.12(d, J=2.5, 1H), 7.11-7.06 (m, 4H), 7.00 (dd, J=8.7, 2.5, 1H), 4.10 (t,J=6.1, 2H), 2.80-2.35 (m, 10H), 2.30 (s, 3H), 2.03-1.98 (m, 2H).

Example 7

1-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine

MS (ESI): mass calcd for C₃₁H₃₅ClN₄O₃, 546.24. m/z found, 547.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.63 (d, J=8.6, 1H), 7.27-7.22 (m, 2H), 7.12(d, J=2.5, 1H), 7.09-7.05 (m, 4H), 7.00 (dd, J=8.7, 2.5, 1H), 6.86-6.84(m, 2H), 4.09 (t, J=6.1, 2H), 3.72 (s, 6H), 2.80-2.35 (m, 10H), 2.29 (s,3H), 2.05-1.95 (m, 2H).

Example 8

1-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-2-fluoro-phenoxy}-propyl)-4-methyl-piperazine

MS (ESI): mass calcd for C₃₁H₃₅FN₄O₃, 530.27. m/z found, 531.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.78-7.71 (m, 2H), 7.28-7.24 (m, 2H), 7.17-7.06(m, 5H), 6.89-6.86 (m, 2H), 4.12 (t, J=6.1, 2H), 3.74 (s, 6H), 2.80-2.35(m, 10H), 2.29 (s, 3H), 2.03-1.99 (m, 2H).

Example 9

1-(3-{4-[4,5-Bis-(4-bromo-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-[1,4]diazepane

MS (ESI): mass calcd for C₃₀H₃₁Br₂ClN₄O, 656.06. m/z found, 659.0[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.52 (d, J=8.6, 1H), 7.40 (d, J=7.6,4H), 7.28 (d, J=8.6, 4H), 7.02 (d, J=2.5, 1H), 6.90 (dd, J=8.6, 4.0,1H), 4.01 (d, J=5.0, 2H), 2.71-2.64 (m, 4H), 2.62-2.55 (m, 6H), 2.25 (s,3H), 1.92-1.81 (m, 2H), 1.78-1.69 (m, 2H).

Example 10

1-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-[1,4]diazepane

MS (ESI): mass calcd for C₃₂H₃₇ClN₄O₃, 560.26. m/z found, 561.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.66 (d, J=8.6, 1H), 7.30-7.23 (m, 2H), 7.14(d, J=2.5, 1H), 7.11-7.08 (m, 4H), 7.02 (dd, J=8.6, 2.5, 1H), 6.90-6.85(m, 2H), 4.12 (t, J=6.3, 2H), 3.75 (s, 6H), 2.83-2.78 (m, 4H), 2.75-2.68(m, 6H), 2.37 (s, 3H), 2.04-1.95 (m, 2H), 1.90-1.83 (m, 2H).

Example 11

1-{3-[2-Chloro-4-(5-methyl-4-phenyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-[1,4]diazepane

MS (ESI): mass calcd for C₂₅H₃₁ClN₄O, 438.22. m/z found, 439.5 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.94 (d, J=2.2, 1H), 7.77 (dd, J=8.6, 2.2, 1H),7.60-7.55 (m, 2H), 7.43-7.39 (m, 2H), 7.29-7.25 (m, 1H), 7.09 (d, J=8.7,1H), 4.11 (t, J=6.0, 2H), 2.78-2.65 (m, 10H), 2.41 (s, 3H), 2.32 (s,3H), 2.01-1.93 (m, 2H), 1.85-1.79 (m, 2H).

Example 12

2-{3-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,5,6,7-tetrahydro-1H-benzoimidazole

MS (ESI): mass calcd for C₂₂H₃₁ClN₄O, 402.22. m/z found, 403.4 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.82 (d, J=2.2, 1H), 7.67 (dd, J=8.6, 2.2, 1H),7.09 (d, J=8.7, 1H), 4.13 (t, J=6.0, 2H), 2.80-2.56 (m, 14H), 2.34 (s,3H), 2.03-1.96 (m, 2H), 1.86-1.80 (m, 6H).

Example 13

2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,5,6,7-tetrahydro-1H-benzoimidazole

MS (ESI): mass calcd for C₂₂H₃₁ClN₄O, 402.22. m/z found, 403.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.47 (d, J=8.7, 1H), 6.93 (d, J=2.5, 1H), 6.83(dd, J=8.7, 2.5, 1H), 3.95 (t, J=6.1, 2H), 2.70-2.47 (m, 14H), 2.25 (s,3H), 1.87-1.80 (m, 2H), 1.74-1.70 (m, 6H).

Example 14

1-Methyl-4-{3-[3-methyl-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperidine

A. 3-(1-Methyl-piperidin-4-yl)-propan-1-ol. To a refluxing solution of 1M LiAlH₄ (40 mmol) in THF (30 mL) was added dropwise a solution ofN—BOC-4-piperidinepropionic acid (3.0 g, 11.6 mmol). The reactionmixture was heated for 3 h then cooled to rt. Upon further cooling to 0°C., water (1.5 mL) was added slowly, and the reaction mixture wasallowed to warm to rt over 15 min. The mixture was again cooled to 0°C., and 10% aq. NaOH (1.5 mL) was added slowly. Upon warming to rt over15 min, the mixture was cooled to 0° C. and more water (4.5 mL) wasadded. The resultant mixture was allowed to warm to rt over 18 h, andwas then filtered through a pad of diatomaceous earth. The filtrate wasconcentrated, and the residue was purified by Method 1 to afford 1.9 g(100%) of 3-(1-methyl-piperidin-4-yl)-propan-1-ol as a yellow oil. MS(ESI): mass calcd for C₉H₁₉NO, 157.15. m/z found 158.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): 3.45-3.41 (m, 2H), 2.77-2.74 (m, 2H), 1.89-1.85 (m,2H), 1.64-1.61 (m, 2H), 1.47-1.43 (m, 2H), 1.21-1.12 (m, 5H).General Procedure 4.B. 4-[3-(1-Methyl-piperidin-4-yl)-propoxy]-benzaldehyde. To anice-cooled solution of 2-methyl-4-hydroxybenzaldehyde (722 mg, 5.3mmol), PPh₃ polymer resin (3 mmol/g, 2.2 g, 6.4 mmol), and3-(1-methyl-piperidin-4-yl)-propan-1-ol (833 mg, 5.3 mmol, 1.0 equiv) inTHF (25 mL) was added di-tert-butyl-azodicarboxylate (1.47 g, 6.4 mmol).The reaction mixture was allowed to warm to rt and was stirred for 16 h.The mixture was filtered through diatomaceous earth, diluted with water,and extracted three times with EtOAc. The combined extracts were dried(Na₂SO₄) and concentrated. Purification by Method 1 afforded 578 mg(40%) of the desired aldehyde. MS (ESI): mass calcd for C₁₆H₂₃NO₂,261.17. m/z found, 262.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 9.85 (s, 1H),7.80 (d, J=8.6, 2H), 6.97 (d, J=8.6, 2H), 4.01 (t, J=6.4, 2H), 2.84-2.82(m, 2H), 2.25 (s, 3H), 1.92-1.78 (m, 4H), 1.71-1.69 (m, 2H), 1.41-1.37(m, 2H), 1.29-1.26 (m, 3H).C.1-Methyl-4-{3-[3-methyl-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperidine.The title compound (27 mg, 21%) was prepared as described in GeneralProcedure 3 with the appropriate substituent changes. MS (ESI): masscalcd for C₂₆H₃₀F₃N₃O, 457.23. m/z found, 458.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): 7.60-7.53 (m, 2H), 7.54-7.44 (m, 4H), 6.91 (d, J=2.3, 1H), 6.87(dd, J=8.5, 2.5, 1H), 4.04 (t, J=6.4, 2H), 2.92-2.89 (m, 2H), 2.47 (s,3H), 2.28 (s, 3H), 2.04-2.00 (m, 2H), 1.86-1.77 (m, 4H), 1.51-1.28 (m,5H).The following compounds in Examples 15-25 were prepared using proceduresanalogous to those described in Example 14 with the appropriatesubstituent changes.

Example 15

4-{3-[3-Chloro-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methyl-piperidine

MS (ESI): mass calcd for C₂₆H₂₇ClF₃N₃O, 477.18. m/z found, 478.3 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.63-7.56 (m, 3H), 7.54-7.44 (m, 3H), 7.13 (d,J=2.5, 1H), 7.01 (dd, J=8.7, 2.5, 1H), 4.05 (t, J=6.4, 2H), 2.92-2.85(m, 2H), 2.28 (s, 3H), 2.07-1.98 (m, 2H), 1.88-1.71 (m, 4H), 1.51-1.41(m, 2H), 1.40-1.22 (m, 3H).

Example 16

4-(3-{3-Chloro-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine

MS (ESI): mass calcd for C₂₆H₂₉ClF₃N₃O, 491.20. m/z found, 492.4 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.97-7.87 (m, 2H), 7.66-7.54 (m, 3H), 7.10 (d,J=2.5, 1H), 6.99 (dd, J=8.8, 2.5, 1H), 4.05 (t, J=6.4, 2H), 2.92-2.85(m, 2H), 2.50 (s, 3H), 2.28 (s, 3H), 2.08-1.95 (m, 2H), 1.88-1.70 (m,4H), 1.59-1.21 (m, 5H).

Example 17

4-(3-{3-Chloro-4-[4-(3,5-dichloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine

MS (ESI): mass calcd for C₂₅H₂₈Cl₃N₃O, 491.13. m/z found, 492.3 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.61-7.54 (m, 3H), 7.32-7.30 (m, 1H), 7.07 (d,J=2.5, 1H), 6.96 (dd, J=8.7, 2.5, 1H), 4.03 (t, J=6.4, 2H), 2.91-2.82(m, 2H), 2.47 (s, 3H), 2.26 (s, 3H), 2.06-1.95 (m, 2H), 1.86-1.66 (m,4H), 1.57-1.17 (m, 5H).

Example 18

4-(3-{4-[4-(3,5-Dichloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-propyl)-1-methyl-piperidine

MS (ESI): mass calcd for C₂₈H₃₁Cl₂N₃O, 471.18. m/z found, 472.3 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.59-7.55 (m, 2H), 7.37 (d, J=8.3, 1H),7.30-7.27 (m, 1H), 7.84 (d, J=2.5, 1H), 6.81 (dd, J=8.6, 2.5, 1H), 3.99(t, J=6.3, 2H), 2.91-2.83 (m, 2H), 2.46 (s, 3H), 2.44 (s, 3H), 2.26 (s,3H), 2.07-1.97 (m, 2H), 1.84-1.72 (m, 4H), 1.46-1.19 (m, 5H).

Example 19

4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine

MS (ESI): mass calcd for C₂₅H₂₉Cl₂N₃O, 457.17. m/z found, 458.3 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.61-7.54 (m, 3H), 7.42-7.37 (m, 2H), 7.06 (d,J=2.5, 1H), 6.95 (dd, J=8.6, 2.3, 1H), 4.01 (t, J=6.3, 2H), 2.90-2.81(m, 2H), 2.43 (s, 3H), 2.25 (s, 3H), 2.05-1.94 (m, 2H), 1.85-1.69 (m,4H), 1.46-1.19 (m, 5H).

Example 20

4-(3-{4-[4,5-Bis-(4-fluoro-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-1-methyl-piperidine

MS (ESI): mass calcd for C₃₀H₃₀ClF₂N₃O, 521.20. m/z found, 522.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.63 (d, J=8.6, 1H), 7.50-7.42 (m, 4H),7.12-7.04 (m, 5H), 6.99 (dd, J=8.6, 2.5, 1H), 4.04 (t, J=6.1, 2H),2.91-2.83 (m, 2H), 2.26 (s, 3H), 2.06-1.95 (m, 2H), 1.87-1.71 (m, 4H),1.48-1.16 (m, 5H).

Example 21

4-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-1-methyl-piperidine

MS (ESI): mass calcd for C₃₂H₃₆ClN₃O₃, 545.24. m/z found, 546.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.62 (d, J=8.6, 1H), 7.27-7.19 (m, 2H),7.10-7.01 (m, 5H), 6.97 (dd, J=8.3, 2.5, 1H), 6.87-6.81 (m, 2H), 4.02(t, J=6.3, 2H), 3.71 (s, 6H), 2.90-2.81 (m, 2H), 2.25 (s, 3H), 2.05-1.94(m, 2H), 1.84-1.70 (m, 4H), 1.47-1.15 (m, 5H).

Example 22

4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-p-tolyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine

MS (ESI): mass calcd for C₃₁H₃₃O₂N₃O, 533.20. m/z found, 534.4 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.62 (d, J=8.6, 1H), 7.49-7.41 (m, 2H),7.36-7.28 (m, 4H), 7.20-7.15 (m, 2H), 7.09 (d, J=2.5, 1H), 6.98 (dd,J=8.6, 2.5, 1H), 4.03 (t, J=6.3, 2H), 2.91-2.83 (m, 2H), 2.35 (s, 3H),2.27 (s, 3H), 2.07-1.97 (m, 2H), 1.86-1.70 (m, 4H), 1.47-1.19 (m, 5H).

Example 23

2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,5,6,7-tetrahydro-1H-benzoimidazole

MS (ESI): mass calcd for C₂₂H₃₀ClN₃O, 387.21. m/z found, 388.3 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.56 (d, J=8.6, 1H), 7.02 (d, J=2.5, 1H), 6.92(dd, J=8.8, 2.5, 1H), 4.01 (t, J=6.3, 2H), 2.95-2.85 (m, 2H), 2.64-2.56(m, 2H), 2.29 (s, 3H), 2.13-2.00 (m, 2H), 1.87-1.00 (m, 15H).

Example 24

4-{3-[3-Chloro-4-(4-methyl-5-propyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methyl-piperidine

MS (ESI): mass calcd for C₂₂H₃₂ClN₃O, 389.22. m/z found, 390.4 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.51 (d, J=8.6, 1H), 7.02 (d, J=2.8, 1H), 6.92(dd, J=9.1, 2.8, 1H), 4.00 (t, J=6.6, 2H), 2.91-2.84 (m, 2H), 2.53 (t,J=7.6, 2H), 2.26 (s, 3H), 2.18 (s, 3H), 2.05-1.96 (m, 2H), 1.84-1.71 (m,4H), 1.67-1.57 (m, 2H), 1.49-1.19 (m, 5H), 0.94 (t, J=7.3, 3H).

Example 25

4-{3-[3-Chloro-4-(5-ethyl-4-methyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methylpiperidine

MS (ESI): mass calcd for C₂₁H₃₀ClN₃O, 375.21. m/z found, 376.4 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.52 (d, J=8.8, 1H), 7.02 (d, J=2.5, 1H), 6.91(dd, J=8.6, 2.5, 1H), 4.00 (t, J=6.6, 2H), 2.95-2.88 (m, 2H), 2.57 (q,J=7.6, 2H), 2.31 (s, 3H), 2.18 (s, 3H), 2.14-2.04 (m, 2H), 1.85-1.73 (m,4H), 1.47-1.23 (m, 5H), 1.20 (t, J=7.6, 3H).

Example 26

1-Methyl-4-(2-{3-methyl-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-ethoxy)-piperidine

This compound was prepared from2-methyl-4-[2-(1-methyl-piperidin-4-yloxy)-ethoxy]-benzaldehyde, usingmethods similar to those described in General Procedure 3. MS (ESI):mass calcd for C₂₆H₃₀F₃N₃O₂, 473.23. m/z found, 474.4 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): 7.93-7.83 (m, 2H), 7.63-7.51 (m, 2H), 7.41 (d, J=7.4,1H), 6.90-6.80 (m, 1H), 6.85 (dd, J=8.3, 2.5, 1H), 4.16-4.11 (m, 2H),3.85-3.79 (m, 2H), 3.54-3.44 (m, 1H), 2.78-2.64 (m, 2H), 2.47 (s, 3H),2.46 (s, 3H), 2.30-2.16 (m, 5H), 1.99-1.88 (m, 2H), 1.72-1.59 (m, 2H).

Example 27

5-[4-(3,5-Dichloro-phenyl)-5-methyl-1H-imidazol-2-yl]-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine

General Procedure 5.

A. 6-[3-(1-Methyl-piperidin-4-yl)-propoxy]-nicotinonitrile. To a stirredsolution of 3-(1-methyl-piperidin-4-yl)-propan-1-ol (5.0 g, 31.7 mmol)in DMF (200 mL), was added NaH (60%; 1.73 g, 43.3 mmol) portion wise.Once the initial effervescence had subsided, the mixture was heated at60° C. for 1 h, and then was cooled to rt. A solution of6-chloronicotinonitrile (4.0 g, 28.9 mmol) in DMF (20 mL) was then addedand the mixture was stirred for 16 h before quenching with saturated(satd.) aq. NaHCO₃ (50 mL) and brine (50 mL). A precipitate was formedand was collected by vacuum filtration to afford 3.67 g of the product.The filtrate was concentrated to half the volume and a second crop ofprecipitate was recovered. The precipitates were combined to give 5.64 g(76%) of an orange solid, which was used without further purification.MS (ESI): mass calcd for C₁₅H₂₁N₃O, 259.17. m/z found, 260.4 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 8.46 (dd, J=2.3, 0.8, 1H), 7.77 (dd, J=8.6, 2.3,1H), 6.80 (dd, J=8.6, 0.8, 1H), 4.34 (t, J=6.6, 2H), 2.96-2.82 (m, 2H),2.25 (s, 3H), 1.92-1.68 (m, 7H), 1.37-1.34 (m, 2H), 0.89-0.81 (m, 2H).General Procedure 6.B. 6-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridine-3-carbaldehyde. To a0° C. solution of6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (640 mg, 2.47mmol) in toluene (20 mL) was added 1.0 M DIBAL-H in hexanes (3.70 mL,3.70 mmol) dropwise. The mixture was warmed to rt and stirred for 2 h(complete by TLC). Methanol was added (5 mL) followed by 1.0 M H₂SO₄ (10mL). After stirring for 30 min the solution was neutralized with satd.aq. NaHCO₃, diluted with satd. aq. sodium potassium tartrate (10 mL),and stirred an additional 30 min. The reaction was extracted with CHCl₃(3×50 mL) and the combined extracts were dried (Na₂SO₄), filtered, andconcentrated, yielding the crude product, which was purified by Method 1to afford 598 mg (92%) of a colorless oil. MS (ESI): mass calcd forC₁₅H₂₂N₂O₂, 262.17. m/z found, 263.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):9.87 (br s, 1H), 8.53 (d, J=2.3, 1H), 7.98 (dd, J=8.6, 2.3, 1H), 6.74(d, J=8.6, 1H), 4.34 (t, J=6.6, 2H), 2.78-2.26 (m, 2H), 2.19 (s, 3H),1.85-1.62 (m, 7H), 1.35-1.16 (m, 4H).C.5-[4-(3,5-Dichloro-phenyl)-5-methyl-1H-imidazol-2-yl]-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine.Preparation by the method described in General Procedure 3 using6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-3-carbaldehyde (70.0mg, 0.26 mmol) gave 10 mg (8.4%) of the title compound. MS (ESI): masscalcd for C₂₄H₂₈Cl₂N₄O, 458.16. m/z found, 459.3 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 9.36 (br s, 1H), 8.49 (s, 1H), 8.12 (dd, J=8.6, 2.3, 1H),7.62 (s, 2H), 7.24 (s, 1H), 6.81 (d, J=8.6, 1H), 4.13 (t, J=6.6, 2H),2.85-2.82 (m, 2H), 2.52, (s, 3H), 2.25 (s, 3H), 1.91-1.68 (m, 7H),1.41-1.36 (m, 2H), 1.29-1.23 (m, 2H).Compounds shown in Examples 28-31 were prepared using methods similar tothose described in General Procedure 3, with the appropriate substituentchanges.

Example 28

5-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine

MS (ESI): mass calcd for C₂₄H₂₉ClN₄O, 424.20. m/z found, 425.4 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 9.06 (br s, 1H), 8.51 (s, 1H), 8.13-8.11 (m,1H), 7.61-7.65 (m, 2H), 7.42-7.36 (m, 2H), 6.81 (d, J=8.6, 1H), 4.13 (t,J=6.6, 2H), 2.86-2.83 (m, 2H), 2.52 (s, 3H), 2.25 (s, 3H), 1.93-1.70 (m,7H), 1.42-1.26 (m, 4H).

Example 29

2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-5-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine

¹H NMR (400 MHz, CDCl₃): 9.17 (br s, 1H), 8.52 (br s, 1H), 8.16-8.13 (m,1H), 8.01-7.91 (m, 1H), 7.91-7.88 (m, 1H), 7.54-7.40 (m, 2H), 6.80 (d,J=8.6, 1H), 4.31 (t, J=6.6, 2H), 2.89-2.87 (m, 2H), 2.54, (s, 3H), 2.28(s, 3H), 1.95-1.69 (m, 7H), 1.44-1.36 (m, 2H), 1.31-1.23 (m, 2H).

Example 30

2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-5-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine

¹H NMR (400 MHz, CDCl₃): 9.36 (br s, 1H), 8.53 (br s, 1H), 8.12 (d,J=8.6, 1H), 7.84 (d, J=7.8, 2H), 7.65 (d, J=7.8, 2H), 6.80 (d, J=8.6,1H), 4.30 (t, J=6.6, 2H), 2.86-2.83 (m, 2H), 2.54, (s, 3H), 2.26 (s,3H), 1.93-1.68 (m, 7H), 1.42-1.36 (m, 2H), 1.30-1.25 (m, 2H).

Example 31

2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-5-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridine

MS (ESI): mass calcd for C₂₄H₂₇F₃N₄O, 444.21. m/z found, 445.4 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.55 (d, J=2.3, 1H), 8.13 (dd, J=8.6, 2.3, 1H),7.54-7.44 (m, 5H), 6.81 (d, J=8.6, 1H), 4.31 (t, J=6.6, 2H), 2.83-2.81(m, 2H), 2.25, (s, 3H), 1.91-1.68 (m, 7H), 1.41-1.36 (m, 2H), 1.28-1.21(m, 2H).

Example 32

1-Methyl-4-(3-{5-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxy}-propyl)-piperazine

A. 6-[3-(4-Methyl-piperazin-1-yl)-propoxy]-nicotinonitrile. Thiscompound was prepared by the method described in General Procedure 5 inExample 27 using 3-(4-methyl-piperazin-1-yl)-propan-1-ol (1.0 g, 6.32mmol), 60% sodium hydride (379 mg, 9.48 mmol), and6-chloronicotinonitrile (876 mg, 6.32 mmol). The reaction mixture waspartitioned between satd. aq. NaHCO₃ (30 mL) and CHCl₃ (60 mL). Theorganic layer was dried (Na₂SO₄), filtered, and concentrated.Purification by Method 1 afforded 776 mg (47%) of a beige solid. MS(ESI): mass calcd for C₁₄H₂₀N₄O, 260.16. m/z found, 261.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.47 (dd, J=2.3, 0.8, 1H), 7.77 (dd, J=8.6, 2.3, 1H),6.80 (dd, J=8.6, 0.8, 1H), 4.41 (t, J=6.6, 2H), 2.76-2.35 (m, 10H), 2.29(s, 3H), 2.01-1.95 (m, 2H).B. 6-[3-(4-Methyl-piperazin-1-yl)-propoxy]-pyridine-3-carbaldehyde. Thiscompound was prepared by the method described in General Procedure 6 inExample 27 using 6-[3-(4-methyl-piperazin-1-yl)-propoxy]-nicotinonitrile(486 mg, 1.86 mmol) and 1.0 M DIBAL-H in hexanes (2.79 mg, 2.79 mmol,1.5 equiv). Purification by Method 1 afforded 225 mg (46%) of acolorless residue. MS (ESI): mass calcd for C₁₄H₂₁N₃O₂, 263.16. m/zfound, 264.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 9.94 (s, 1H), 8.61 (d,J=2.3, 1H), 8.06 (dd, J=8.6, 2.3, 1H), 6.82 (d, J=8.6, 1H), 4.46 (t,J=6.6, 2H), 2.64-2.33 (m, 10H), 2.29 (s, 3H), 2.03-1.96 (m, 2H).C.1-Methyl-4-(3-{5-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxy}-propyl)-piperazine.Preparation by the method described in General Procedure 3 withappropriate substituent changes provided 13 mg (17%) of the titlecompound. MS (ESI): mass calcd for C₂₄H₂₈F₃N₅O, 459.22; m/z found, 460.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 9.86 (br s, 1H), 8.51 (s, 1H), 8.09 (d,J=8.6, 1H), 7.84-7.74 (br s, 2H), 7.64 (d, J=7.8, 2H), 6.77 (d, J=8.6,1H), 4.34 (t, J=6.6, 2H), 2.60-2.39 (m, 13H), 2.28 (s, 3H), 2.02-1.94(m, 2H).

Example 33

1-Methyl-4-(3-{5-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxy}-propyl)-piperazine

Preparation by the method described in General Procedure 3 withappropriate substituent changes afforded 7 mg (9%) of the titlecompound. MS (ESI): mass calcd for C₂₄H₂₈F₃N₅O, 459.22. m/z found, 460.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 9.34 (br s, 1H), 8.51 (s, 1H), 8.14 (d,J=8.6, 1H), 8.04-7.83 (br s, 2H), 7.66-7.52 (m, 2H), 6.80 (d, J=8.6,1H), 4.38 (t, J=6.6, 2H), 2.57-2.37 (m, 13H), 2.30 (s, 3H), 2.02-1.95(m, 2H).

Example 34

4-(4-{3-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-butyl)-1-methyl-piperidine

A. 3-[4-(1-Methyl-piperidin-4-yl)-butoxy]-benzonitrile. To a 0° C.solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (0.74 g, 4.37 mmol),3-hydroxy-benzonitrile (0.52 g, 4.37 mmol), and 3 mmol/g polymersupported PPh₃ (2.30 g, 8.73 mmol) in THF (40 mL) was added diisopropylazodicarboxylate (1.72 mL, 8.73 mmol) dropwise. After 6 h the mixturewas filtered and concentrated. Purification by Method 1 afforded 840 mg(71%) of a yellow oil. MS (ESI): mass calcd for C₁₇H₂₄N₂O, 272.19. m/zfound, 273.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.38-7.33 (m, 1H),7.24-7.20 (m, 1H), 7.14-7.09 (m, 2H), 3.96 (t, J=6.4, 2H), 2.88-2.80 (m,2H), 2.26 (s, 3H), 1.94-1.84 (m, 2H), 1.82-1.73 (m, 2H), 1.72-1.64 (m,2H), 1.52-1.42 (m, 2H), 1.34-1.17 (m, 5H).B. 3-[4-(1-Methyl-piperidin-4-yl)-butoxy]-benzaldehyde. To a stirredsolution of 3-[4-(1-methyl-piperidin-4-yl)butoxy]-benzonitrile (0.84 g,3.09 mmol) in toluene (5 mL) at 0° C. was added 1.5 M DIBAL-H in toluene(4.63 mL, 4.63 mmol). After 3 h, methanol (9 mL) and 1.0 M H₂SO₄ (10 mL)were added dropwise. After stirring for 30 min, the solution wasneutralized with 1.0 M sodium hydroxide (10 mL) followed by addition ofsatd. aq. sodium potassium tartrate (40 mL) and CH₂Cl₂ (100 mL). Afterstirring for 30 min the solution was extracted with CHCl₃ (3×50 mL),washed with brine and dried over Na₂SO₄. Purification by Method 1afforded 0.56 g (66%) of the title compound. ¹H NMR (400 MHz, CDCl₃):9.97 (s, 1H), 7.46-7.43 (m, 2H), 7.39-7.37 (m, 1H), 7.19-7.15 (m, 1H),4.02 (t, J=6.6, 2H), 2.86-2.80 (m, 2H), 2.25 (s, 3H), 1.92-1.83 (m, 2H),1.83-1.75 (m, 2H), 1.73-1.63 (m, 2H), 1.54-1.44 (m, 2H), 1.34-1.18 (m,5H).C.4-(4-{3-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-butyl)-1-methyl-piperidine.Preparation using the method described in General Procedure 3 afforded49 mg (28%) of the title compound. MS (ESI): mass calcd for C₂₆H₃₂ClN₃O,437.22. m/z found, 438.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 10.2 (br s,1H), 7.64 (br s, 1H), 7.48-7.44 (m, 1H), 7.41-7.26 (m, 4H), 7.31-7.27(m, 1H), 6.88-6.84 (m, 1H), 3.95-3.85 (m, 2H), 2.85-2.77 (m, 2H), 2.43(s, 3H), 2.25 (s, 3H), 1.93-1.82 (m, 2H), 1.76-1.60 (m, 4H), 1.45-1.35(m, 2H), 1.30-1.15 (m, 5H).

Example 35

1-Methyl-4-{4-[3-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-butyl}-piperidine

This compound was prepared using methods similar to those described inExample 34 with the appropriate substituent changes. MS (ESI): masscalcd for C₂₆H₃₀F₃N₃O, 457.23. m/z found 458.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): 7.51-7.28 (m, 8H), 6.96-6.91 (m, 1H), 3.93 (t, J=5.8, 2H),2.79-2.71 (m, 2H), 2.23 (s, 3H), 1.88-1.80 (m, 2H), 1.77-1.68 (m, 2H),1.66-1.56 (m, 2H), 1.46-1.11 (m, 7H).

Example 36

2-[4-(1-Methyl-piperidin-4-yl)-butoxy]-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridine

A. 2-[4-(1-Methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile. To astirred solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (1.0 g, 5.85mmol) in DMF (12 mL) at 0° C. was added NaH (60%; 280 mg, 7.02 mmol).The mixture was warmed to rt for 1 h, then cooled to 0° C. A solution of2-chloro-isonicotinonitrile (810 mg, 5.85 mmol) in DMF (4 mL) was addeddropwise. The mixture was stirred at rt for 18 h, and then was dilutedwith water (5 mL) and satd. aq. NaHCO₃ (25 mL). The mixture wasextracted with CHCl₃ (3×25 mL), dried (Na₂SO₄), filtered, and.Purification by Method 1 afforded 440 mg (28%) of a yellow oil. MS(ESI): mass calcd for C₁₆H₂₃N₃O, 273.18. m/z found, 274.4 [M+H]⁺.B. 2-[4-(1-Methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbaldehyde. To astirred solution of2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile (0.44 g, 1.61mmol) in toluene (5 mL) at 0° C. was added a 1.5 M DIBAL-H in toluene(2.41 mL, 2.41 mmol). The reaction mixture was allowed to warm to rt.After 3 h, methanol (8 mL) and 1.0 M H₂SO₄ (5 mL) were added dropwise.After 30 min, the mixture was neutralized with 1.0 M NaOH (10 mL)followed by addition of satd. aq. sodium potassium tartrate (40 mL) andCH₂Cl₂ (100 mL). After 30 min the mixture was extracted with CHCl₃ (3×50mL) and washed with brine. The organic layer was dried (Na₂SO₄),filtered, and concentrated. Purification of the mixture by Method 1afforded 318 mg (64%) of the title compound. ¹H NMR (400 MHz, CDCl₃):10.0 (s, 1H), 8.34 (d, J=5.3, 1H), 7.28 (d, J=1.3, 1H), 7.14-7.12 (m,1H), 4.33 (t, J=6.6, 2H), 2.87-2.80 (m, 2H), 2.25 (s, 3H), 1.93-1.65 (m,6H), 1.52-1.42 (m, 2H), 1.35-1.07 (m, 5H).C.2-[4-(1-Methyl-piperidin-4-yl)-butoxy]-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridine.Preparation according to the method described in General Procedure 3afforded 27.9 mg (36%) of the title compound. MS (ESI): mass calcd forC₂₅H₂₉F₃N₄O, 458.23. m/z found, 459.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):8.20 (d, J=5.3, 0.5, 1H), 7.61-7.54 (m, 2H), 7.54-7.45 (m, 4H),7.39-7.35 (m, 1H), 4.3 (t, J=6.4, 2H), 2.95-2.83 (m, 2H), 2.28 (s, 3H),2.10-1.99 (m, 2H), 1.84-1.66 (m, 4H), 1.56-1.43 (m, 2H), 1.39-1.14 (m,5H).

Example 37

2-[4-(1-Methyl-piperidin-4-yl)-butoxy]-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine

This compound was prepared using methods similar to those described inExample 36 with the appropriate substituent changes. MS (ESI): masscalcd for C₂₆H₃₁F₃N₄O, 472.24. m/z found, 473.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): 8.16 (d, J=5.3, 1H), 7.95 (m, 2H), 7.91-7.86 (m, 2H), 7.45 (dd,J=5.5, 1.5, 1H), 7.30-7.26 (m, 1H), 4.29 (t, J=6.3, 2H), 2.89-2.80 (m,2H), 2.49 (s, 3H), 2.25 (s, 3H), 2.03-1.92 (m, 2H), 1.82-1.66 (m, 4H),1.55-1.44 (m, 2H), 1.36-1.16 (m, 5H).

Example 38

4-{3-[4-(5-Isobutyl-4-methyl-1H-imidazol-2-yl)-3-methyl-phenoxy]-propyl}-1-methyl-piperidine

This compound was prepared using methods similar to those described inExample 14 with the appropriate substituent changes. MS (ESI): masscalcd for C₂₄H₃₇N₃O, 383.29. m/z found, 384.5 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): 7.29 (d, J=8.3, 1H), 6.83-6.74 (m, 2H), 3.97 (t, J=6.6, 2H),2.91-2.81 (m, 2H), 2.40 (d, J=7.3, 2H), 2.36 (s, 3H), 2.26 (s, 3H), 2.16(s, 3H), 2.06-1.62 (m, 7H), 1.49-1.16 (m, 5H), 0.93 (d, J=6.8, 6H).

Example 39

4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine

This compound was prepared using methods similar to those described inExample 36 with the appropriate substituent changes. MS (ESI): masscalcd for C₂₅H₃₁ClN₄O, 438.22. m/z found, 439.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): 8.18 (d, J=5.6, 1H), 7.67-7.61 (m, 2H), 7.49-7.44 (m, 3H),7.32-7.30 (m, 1H), 4.35-4.29 (m, 2H), 2.99-2.91 (m, 2H), 2.47 (s, 3H),2.34 (s, 3H), 2.18-2.08 (m, 2H), 1.84-1.22 (m, 11H).

Example 40

4-{3-[3-Chloro-4-(5-isobutyl-4-methyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methyl-piperidine

This compound was prepared using methods similar to those described inExample 14 with the appropriate substituent changes. MS (ESI): masscalcd for C₂₃H₃₄ClN₃O, 403.24. m/z found, 404.5 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 9.91-9.60 (br s, 1H), 8.16-8.11 (m, 1H), 6.92-6.83 (m, 2H),3.97-3.92 (m, 2H), 2.88-2.81 (m, 2H), 2.50-2.38 (m, 2H), 2.27-2.20 (m,6H), 2.08-1.66 (m, 7H), 1.43-1.18 (m, 5H), 0.99-0.89 (m, 6H).

Example 41

1-Methyl-4-(4-{3-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-butyl)-piperidine

This compound was prepared using methods similar to those described inExample 36 with the appropriate substituent changes. MS (ESI): masscalcd for C₂₇H₃₂F₃N₃O, 471.25. m/z found 472.4 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 9.87 (s, 1H), 7.92-7.50 (m, 4H), 7.48-7.45 (m, 1H), 7.40-7.36(m, 1H), 7.34-7.28 (m, 1H), 6.89 (dd, J=8.1, 2.0, 1H), 3.99-3.91 (m,2H), 2.86-2.79 (m, 2H), 2.50 (s, 3H), 2.25 (s, 3H), 1.91-1.85 (m, 2H),1.78-1.60 (m, 4H), 1.48-1.37 (m, 2H), 1.32-1.15 (m, 5H).Examples 42-45 were prepared using methods similar to those described inExample 1 with the appropriate substituent changes.

Example 42

1-{3-[2-Chloro-4-(1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine

MS (ESI): mass calcd for C₁₇H₂₃ClN₄O, 334.16. m/z found, 335.3 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.89 (d, J=2.2, 1H), 7.74 (dd, J=8.6, 2.2, 1H),7.15 (d, J=8.6, 1H), 7.09 (br s, 2H), 4.16 (t, J=6.0, 2H), 2.75-2.35 (m,10H), 2.29 (s, 3H), 2.06-2.02 (m, 2H).

Example 43

1-{3-[3-Chloro-4-(4,5-dimethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine

MS (ESI): mass calcd for C₁₉H₂₇ClN₄O, 362.19. m/z found, 363.4 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.54 (d, J=8.7, 1H), 7.05 (d, J=2.5, 1H), 6.93(dd, J=8.5, 2.5, 1H), 4.07 (t, J=6.1, 2H), 2.75-2.35 (m, 10H), 2.29 (s,3H), 2.17 (s, 6H), 2.00-1.98 (m, 2H).

Example 44

1-{3-[3-Chloro-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine

MS (ESI): mass calcd for C₂₄H₂₆ClF₃N₄O, 478.17. m/z found, 479.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.61-7.57 (m, 3H), 7.53-7.45 (m, 3H), 7.15 (d,J=2.5, 1H), 7.03 (dd, J=8.7, 2.5, 1H), 4.11 (t, J=6.1, 2H), 2.75-2.35(m, 10H), 2.31 (s, 3H), 2.04-2.00 (m, 2H).

Example 45

1-{3-[2-Chloro-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-[1,4]diazepane

MS (ESI): mass calcd for C₂₅H₂₈ClF₃N₄O, 492.19. m/z found, 493.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.91 (d, J=2.2, 1H), 7.76 (dd, J=8.6, 2.2, 1H),7.47-7.33 (m, 5H), 7.05 (d, J=8.7, 1H), 4.05 (t, J=6.0, 2H), 2.71-2.60(m, 10H), 2.26 (s, 3H), 1.91-1.88 (m, 2H), 1.75-1.72 (m, 2H).

Examples 46-47 were prepared using methods similar to those described inExample 14 with the appropriate substituent changes.

Example 46

1-Methyl-4-(3-{3-methyl-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-propyl)-piperidine

MS (ESI): mass calcd for C₂₇H₃₂F₃N₃O, 471.25. m/z found, 472.4 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.94-7.87 (m, 2H), 7.63-7.54 (m, 2H), 7.42 (d,J=8.4, 1H), 6.88-6.82 (m, 2H), 4.01 (t, J=6.3, 2H), 2.96-2.82 (m, 2H),2.49 (s, 3H), 2.47 (s, 3H), 2.28 (s, 3H), 2.09-2.00 (m, 2H), 1.88-1.72(m, 4H), 1.52-1.42 (m, 2H), 1.40-1.21 (m, 3H).

Example 47

4-(3-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-propyl)-1-methyl-piperidine

MS (ESI): mass calcd for C₂₆H₃₂ClN₃O, 437.22. m/z found, 438.4 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.60-7.56 (m, 2H), 7.43-7.37 (m, 3H), 6.86 (d,J=2.4, 1H), 6.82 (dd, J=8.5, 2.5, 1H), 4.00 (t, J=6.4, 2H), 2.93-2.83(m, 2H), 2.45 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 2.08-1.96 (m, 2H),1.83-1.72 (m, 4H), 1.49-1.39 (m, 2H), 1.38-1.20 (m, 3H).

Example 48

4-(2-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-ethoxy)-1-methyl-piperidine

The title compound was prepared using methods similar to those describedin General Procedure 3 using2-methyl-4-[2-(1-methyl-piperidin-4-yloxy)-ethoxy]-benzaldehyde. MS(ESI): mass calcd for C₂₅H₃₀ClN₃O₂, 439.98. m/z found, 440.3 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): 7.62-7.52 (m, 2H), 7.43-7.33 (m, 3H), 6.91-6.80(m, 2H), 4.17-4.07 (m, 2H), 3.86-3.76 (m, 2H), 3.48 (br s, 1H),2.78-2.63 (m, 2H), 2.44 (s, 3H), 2.42 (s, 3H), 2.30-2.15 (m, 5H),1.98-1.86 (m, 2H), 1.72-1.58 (m, 2H).Examples 49-68 are prepared using methods similar to those described inExamples 1-48.

Example 49

1-(3-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-2-methyl-propyl)-4-methyl-piperazineExample 50

2-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-6-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridineExample 514-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-5-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridineExample 52

5-Bromo-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridineExample 53

2,4-Dimethyl-1-{3-[4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperazineExample 54

1,2-Dimethyl-4-{3-[4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperazineExample 55

3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridineExample 56

1-Methyl-4-(4-{4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxy}-butyl)-[1,4]diazepaneExample 57

5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridineExample 58

4-[4-(4-Chloro-phenyl)-5-trifluoromethyl-1H-imidazol-2-yl]-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyrimidineExample 59

4-(3-{4-[5-Cyclopropylmethyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-3-methyl-phenoxy}-propyl)-1-methyl-piperidineExample 60

1-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-3-(4-methyl-piperazin-1-yl)-propan-2-olExample 61

4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]phenoxy}-propyl)-piperidineExample 62

4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]phenoxy}-propyl)-1-ethyl-piperidineExample 63

4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]phenoxy}-propyl)-1-isopropyl-piperidineExample 64

1-Methyl-4-{3-[4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-naphthalen-1-yloxy]-propyl}-piperidineExample 65

1-(4-Methyl-piperazin-1-yl)-3-{5-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxy}-propan-1-oneExample 66

6-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-fluoro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridineExample 67

1-Methyl-4-(4-{3-methyl-6-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxy}-butyl)-piperazineExample 68

1-Methyl-4-{3-[4-(5-methyl-4-thiophen-2-yl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperidineExample 69

2-{3-[4-(1-Methyl-piperidin-4-yl)-butoxy]-phenyl}-3H-imidazo[4,5-b]pyridine

The title compound was prepared using methods similar to those describedin Example 1. MS (ESI): mass calcd for C₂₂H₂₈N₄O, 364.48. m/z found,365.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.30-8.22 (dd, J=4.9, 1.5, 1H),7.95-7.86 (dd, J=8.0, 1.4, 1H), 7.67-7.57 (m, 2H), 7.42-7.30 (m, 1H),7.26-7.16 (m, 1H), 7.05-6.95 (dd, J=8.2, 2.4, 1H), 4.07-3.93 (t, J=6.3,2H), 2.84-2.70 (m, 2H), 2.18-2.12 (s, 3H), 2.00-1.82 (m, 2H), 1.79-1.56(m, 4H), 1.52-1.37 (m, 2H), 1.32-1.01 (m, 5H).

Biological Examples Binding Assay on Recombinant Human Histamine H₄Receptor

SK-N-MC cells or COS7 cells were transiently transfected with pH4R andgrown in 150 cm² tissue culture dishes. Cells were washed with salinesolution, scraped with a cell scraper and collected by centrifugation(1000 rpm, 5 min). Cell membranes were prepared by homogenization of thecell pellet in 20 mM Tris-HCl with a polytron tissue homogenizer for 10sec at high speed. Homogenate was centrifuged at 1000 rpm for 5 min at4° C. The supernatant was then collected and centrifuged at 20,000×g for25 min at 4° C. The final pellet was resuspended in 50 mM Tris-HCl. Cellmembranes were incubated with ³H-histamine (5-70 nM) in the presence orabsence of excess histamine (10,000 nM). Incubation occurred at roomtemperature for 45 min. Membranes were harvested by rapid filtrationover Whatman GF/C filters and washed 4 times with ice-cold 50 mM TrisHCl. Filters were then dried, mixed with scintillant and counted forradioactivity. SK-N-MC or COS7 cells expressing human histamine H₄receptor were used to measure the affinity of binding of other compoundsand their ability to displace ³H-ligand binding by incubating theabove-described reaction in the presence of various concentrations ofinhibitor or compound to be tested. For competition binding studiesusing ³H-histamine, K_(i) values were calculated, based on anexperimentally determined K_(D) value of 5 nM and a ligand concentrationof 5 nM, according to Y.-C. Cheng and W. H. Prusoff (Biochem. Pharmacol.1973, 22(23):3099-3108): K_(i)=(IC₅₀)/(1+([L]/(K_(D))).

Binding Assay Results

TABLE 1 EX K_(i) (nM) 1 14 2 39 3 244 4 44 5 24 6 29 7 21 8 60 9 11 10 611 70 12 65 13 32 14 32 15 38 16 165 17 52 18 45 19 22 20 39 21 37 22 2923 155 24 69 25 100 26 300 27 290 28 72 29 42 30 64 31 186 32 230 33 6334 33 35 57 36 54 37 174 38 230 39 230 40 93 41 250 42 1963 43 2510 4420 45 79 46 16 47 33 48 620 69 1413Mast Cell Chemotaxis Assay

Mast cell accumulation in mucosal epithelia is a well-knowncharacteristic of allergic rhinitis and asthma. In addition, it is knownthat mast cell numbers increase in a number of inflammatory conditions.Some of this is due to chemotaxis of mast cells to the sites ofinflammation. This chemotaxis to specific agents can be mimicked invitro. Transwells (Costar, Cambridge, Mass.) of a pore size 8 μm werecoated with 1004 of 100 ng/mL human fibronectin (Sigma) for 2 h at roomtemperature. After removal of the fibronectin, 600 μL of RPMI with 5%BSA, in the presence of 10 μM histamine, was added to the bottomchamber. To test the various histamine receptor (HR) antagonists, 10 μMand/or 1 μM solutions of the test compounds were added to the top andbottom chambers. Mast cells (2×10⁵/well) were added to the top chamber.The plates were incubated for 3 h at 37° C. Transwells were removed andthe cells in the bottom chamber were counted for sixty seconds using aflow cytometer. Histamine receptor (HR) inhibition data were thusobtained.

Cell-Type Distribution of H₄ Expression

RNA was prepared from the different cells using an RNeasy kit (Qiagen,Valencia, Calif.) according to the manufacturer's instructions. TotalRNA was extracted from purified human cells using the RNeasy kit(Qiagen, Valencia, Calif.) and reverse transcribed to cDNA using the RTreaction kit (Invitrogen) according to the manufacturer's instructions.H₄ receptor RNA was detected by RT-PCR using human H₄ receptor-specificprimers 5′-ATGCCAGATACTAATAGCACA (SEQ ID NO.:1) and5′-CAGTCGGTCAGTATCTTCT (SEQ ID NO.:2). The amplified PCR band for H₄receptor is 1170 bp.

Results

The RT-PCR results indicated that the H₄ receptor is expressed on mastcells, dendritic cells, basophils, and eosinophils. These positiveresults are consistent with the published literature (e.g. Oda et al.,Nguyen et al., and Morse et al. in the Background section). Accumulationof mast cells and eosinophils in affected tissues is one of theprincipal characteristics of allergic rhinitis and asthma. Since H₄receptor expression is found in these cell types, H₄ receptor signallingis likely to mediate the infiltration of mast cells and eosinophils inresponse to histamine. The following table reports the Cell-typeDistribution of H₄ Expression by RT-PCR. A (+) indicates the presence ofH₄ receptors; a (−) indicates the absense of H₄ receptors.

TABLE 2 Species Cell Type H₄ Human Eosinophils + Immature DendriticCells + Mature Dendritic Cells + Mast Cells + Basophils + CD14⁺Monocytes − CD4⁺ T Cells + CD8⁺ T Cells − B Cells − Neutrophils −Mouse/(Rat) Eosinophils + Peritoneal Mast Cells (Rat) + BoneMarrow-Derived + Mast Cells Immature Dendritic Cells + Mature DendriticCells + Bone Marrow-Derived − Macrophages Peritoneal Macrophages − CD4⁺T Cells − CD8⁺ T Cells − B Cells −The Inhibition of Eosinophil Shape Change by Histamine H₄ ReceptorAntagonists

Eosinophil accumulation in sites of allergic reaction is a well-knowncharacteristic of allergic rhinitis and asthma. This exampledemonstrates that histamine H₄ receptor antagonists can block the shapechange response in human eosinophils in response to histamine. Shapechange is a cellular characteristic that precedes eosinophil chemotaxis.

Methods

Human granulocytes were isolated from human blood by a Ficoll gradient.The red blood cells were lysed with 5-10× Qiagen lysis buffer at roomtemperature for 5-7 min. Granulocytes were harvested and washed oncewith FACS buffer. The cells were resuspended at a density of 2×10⁶cells/mL in reaction buffer. To test inhibition by specific histaminereceptor antagonists, 90 μL of the cell suspension (˜2×10⁵ cells) wasincubated with 10 μM of one of the various test compound solutions.After 30 min, 11 μL of one of the various concentrations of histaminewas added. Ten minutes later the cells were transferred to ice and fixedwith 250 μL of ice-cold fixative buffer (2% formaldehyde) for 1 min. Theshape change was quantitated using a gated autofluorescence forwardscatter assay (GAFS) (S. A. Bryan et al., Am. J. Respir. Crit. Care Med.2002, 165(12):1602-1609).

Results—Histamine Mediates Eosinophil Shape Change Through H₄ Receptor

The change in shape of eosinophils is due to cytoskeletal changes thatprecede chemotaxis and thus is a measure of chemotaxis. The data in thefollowing table show that histamine induces a dose-dependent shapechange in eosinophils. Histamine receptor (HR) antagonists were used tosort out which histamine receptor is responsible for the shape change.Antagonists specific for the histamine H₁ receptor (diphenhydramine) orthe H₂ receptor (ranatidine) did not alter the histamine-induced shapechange. However, a dual H₃/H₄ antagonist (thioperamide) and a specifichistamine H₄ receptor antagonist((5-chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone, K_(i)=5nM) inhibited histamine-induced eosinophil shape change with an IC₅₀ of1.5 and 0.27 μM, respectively.

TABLE 3 Histamine Fold Change (μM): 10 1 0.1 0.01 0 No HR 1.34 1.31 1.211.01 1.00 Antagonist 10 μM H₄ 1.09 1.05 1.05 1.01 1.00 Antagonist 10 μM1.08 1.05 1.01 1.04 1.00 Thiop 10 μM 1.63 1.50 1.18 1.03 1.00 Diphen 10μM 1.64 1.49 1.21 1.04 1.00 RanatThe Inhibition of Eosinophil Chemotaxis by Histamine H₄ ReceptorAntagonists

Eosinophil accumulation in sites of allergic reaction is a well-knowncharacteristic of allergic rhinitis and asthma. Eosinophils werepurified from human blood with standard methods. Chemotaxis assays werecarried out using transwells (Costar, Cambridge, Mass.) of a pore size 5μm coated with 100 μL of 100 ng/mL human fibronectin (Sigma) for 2 h atroom temperature. After removal of the fibronectin, 600 μL of RPMI with5% BSA in the presence of histamine (ranging from 1.25-20 μM) was addedto the bottom chamber. To test the various histamine receptorantagonists 10 μM of the test compounds were added to the top and bottomchambers. Eosinophils were added to the top chamber whereas histamine orchemotactic factors were placed in the lower chamber. The plates wereincubated for 3 h at 37° C. Transwells were removed and the number ofcells in the bottom chamber were counted for 60 s using a flowcytometer, or were quantitated by using Giemsa staining.

Inhibition of Mast Cell Chemotaxis by H₄ Receptor Antagonist in anAnimal Model of Asthma and Allergic Rhinitis

An animal model was used to test the observation that mast cellsaccumulate in response to allergic inflammation and that thisaccumulation can be blocked by H₄ receptor antagonists. Compounds of thepresent invention were tested in this model to demonstrate their use astreatments for allergic rhinitis or asthma. Mice were sensitized byintraperitoneal injection of ovalbumin/Alum (10 μg in 0.2 ml Al(OH)₃,2%) on Day 0 and Day 14. On Day 21 through 23 mice were challenged byPBS or ovalbumin, and sacrificed 24 h after the last challenge on Day24. A section of the trachea was removed and fixed in formalin. Paraffinembedding and longitudinal sectioning of tracheas were performedfollowed by staining of mast cells with toluidine blue. Alternatively,trachea were frozen in OCT for frozen sectioning, and mast cells wereidentified by IgE staining. Mast cells were quantified as sub-mucosal orsub-epithelial depending on their location within each tracheal section.Exposure to allergen should increase the number of sub-epithelial mastcells, and this effect is blocked by H₄ receptor antagonists.

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. Publications describedherein are incorporated by reference in their entirety. These otherembodiments are also within the scope of the invention.

1. A compound of formula (I):

wherein X is, independently from other member and substituentassignments, CR⁹; Y is, independently from other member and substituentassignments, O, NR¹⁰, or CR¹⁰R¹¹; Z is, independently from other memberand substituent assignments, CR¹²; n is, independently from other memberand substituent assignments, 1; each of R¹⁻² is, independently fromother member and substituent assignments, —H, —CF₃, —C₁₋₆alkyl,—C₃₋₆cycloalkyl, optionally substituted aryl or optionally substitutedheteroaryl; or, R¹ and R² taken together with the carbon atoms to whichthey are attached form a cyclic structure Cyc1 selected from 5- or6-membered carbocycle, wherein said cyclic structure Cyc1 is,independently from other substituent assignments, substituted with 0, 1,or 2 substituents selected from —C₁₋₃alkyl, halo, hydroxy, amino, and—C₁₋₃alkoxy; each of R³⁻⁴ and R⁹ is, independently from other member andsubstituent assignments, —H, —C₁₋₆alkyl, halo, —CF₃, —OCF₃, —OR^(c),—SR^(c), —S(O)R^(c), —SO₂R^(c), C₁₋₄alkoxy, cyano, nitro,—C(O)NR^(a)R^(b), —C(O)phenyl, —C(O)C₁₋₆alkyl, —S(O)C₁₋₄-alkyl, or—SO₂C₁₋₄alkyl; or, R³ and R⁴ taken together with the carbon atoms towhich they are attached form a cyclic structure Cyc2 selected from aryl,5- or 6-membered carbocycle, and 5- or 6-membered heterocycle with 1 or2 heteroatoms, wherein said cyclic structure Cyc2 is, independently fromother substituent assignments, substituted with 0, 1, or 2 substituentsselected from —C₁₋₃alkyl, halo, hydroxy, amino, and —C₁₋₃alkoxy; whereineach of R^(a), R^(b) and R^(c) is, independently from other substituentassignments, selected from H, C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl,(C₃₋₆cycloalkyl)C₁₋₂alkyl-, benzyl and phenethyl, or R^(a) and R^(b)taken together with the nitrogen to which they are attached, form a 4-7membered heterocyclic ring HetCyc1, wherein said ring HetCyc1 has 0 or 1additional heteroatoms selected from O, S, >NH and >NC₁₋₆alkyl, andwherein any phenyl, phenethyl, benzyl, alkyl or cycloalkyl moiety in anyof said R¹⁻⁴, R^(a), R^(b), R^(c), and said ring HetCyc1 is optionally,and independently from other substituent assignments, substituted with1, 2 or 3 substituents selected from C₁₋₃alkyl, halo, hydroxy, amino,and C₁₋₃alkoxy; R⁵ is, independently from other member and substituentassignments, —H, —C₁₋₆alkyl, —C₁₋₄-alkoxy, or hydroxy; each of R⁶ and R⁷is, independently from other member and substituent assignments, —H or—C₁₋₆alkyl; R⁸ is, independently from other member and substituentassignments, —H or —C₁₋₄alkyl; each of R¹⁰ and R¹¹ is, independentlyfrom other member and substituent assignments, —H or —C₁₋₄alkyl; or,when Y is CR¹⁰R¹¹, R¹⁰ and R¹¹ taken together with the carbon member towhich they are attached form an optionally substituted cyclic structureCyc4, wherein said cyclic structure Cyc4 is a 3- to 6-memberedcarbocycle or a 3- to 6-membered non-aromatic heterocycle with 0 or 1additional heteroatoms, or CR¹⁰R¹¹ is C═O; R¹² is, independently fromother member and substituent assignments, —H, —C₁₋₄alkyl, hydroxy, or—C₁₋₄alkoxy; an enantiomer, diastereomer, racemate thereof, or apharmaceutically acceptable salt, amide or ester thereof; with thefollowing provisos: when Y is O or NR¹⁰, then Z is CR¹² and R⁵ is nothydroxy or —C₁₋₄alkoxy; when R¹ and R² are both —H, Y is CH₂, and R⁸ ismethyl, then R⁵ is not hydroxy.
 2. A compound of claim 1, wherein Y isCR¹⁰R¹¹.
 3. A compound of claim 1, wherein Y is CH₂.
 4. A compound ofclaim 1, wherein one or both of R¹ and R² are a mono- or di-substitutedphenyl ring.
 5. A compound of claim 1, wherein only one of R¹ or R² is amono-substituted phenyl ring.
 6. A compound of claim 1, wherein R³ is—H, —F, —Cl, methyl, or ethyl.
 7. A compound of claim 1, wherein R³ is—F, —Cl, or methyl.
 8. A compound of claim 1, wherein R³ is —Cl ormethyl.
 9. A compound of claim 1, wherein R⁴ is —H, —F, —Cl, or methyl.10. A compound of claim 1, wherein R⁵ is —H, methyl, or hydroxy.
 11. Acompound of claim 1, wherein R⁵ is —H.
 12. A compound of claim 1,wherein R⁶ and R⁷ are, independently, selected from the group consistingof a) —H, and b) methyl, ethyl, propyl, and isopropyl.
 13. A compound ofclaim 1, wherein R⁶ and R⁷ are, independently, —H or methyl.
 14. Acompound of claim 1, wherein R⁸ is —H, methyl, or ethyl.
 15. A compoundof claim 1, wherein R⁸ is methyl.
 16. A compound of claim 1, wherein R⁹is —H, —F, —Cl, or methyl.
 17. A compound selected from:1-Methyl-4-{3-[3-methyl-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperidine;4-{3-[3-Chloro-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methyl-piperidine;4-(3-{3-Chloro-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{3-Chloro-4-[4-(3,5-dichloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{4-[4-(3,5-Dichloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{4-[4,5-Bis-(4-fluoro-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-p-tolyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine;2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,5,6,7-tetrahydro-1H-benzoimidazole;4-{3-[3-Chloro-4-(4-methyl-5-propyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methyl-piperidine;4-{3-[3-Chloro-4-(5-ethyl-4-methyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methylpiperidine;1-Methyl-4-(2-{3-methyl-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-ethoxy)piperidine;4-{3-[4-(5-Isobutyl-4-methyl-1H-imidazol-2-yl)-3-methyl-phenoxy]-propyl}-1-methyl-piperidine;4-{3-[3-Chloro-4-(5-isobutyl-4-methyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methyl-piperidine;1-Methyl-4-(3-{3-methyl-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-propyl)-piperidine;4-(3-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-propyl)-1-methyl-piperidine;4-(2-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-ethoxy)-1-methyl-piperidine;4-(3-{4-[5-Cyclopropylmethyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-3-methyl-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-piperidine;4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-ethyl-piperidine;4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-isopropyl-piperidine;1-Methyl-4-{3-[4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-naphthalen-1-yloxy]-propyl}-piperidine;1-Methyl-4-{3-[4-(5-methyl-4-thiophen-2-yl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperidine;and pharmaceutically acceptable salts thereof.
 18. A pharmaceuticalcomposition, comprising at least one compound as claimed in claim
 1. 19.A pharmaceutical composition, comprising at least one compound asclaimed in claim
 2. 20. A pharmaceutical composition, comprising atleast one compound as claimed in claim
 3. 21. A pharmaceuticalcomposition, comprising at least one compound as claimed in claim
 4. 22.A pharmaceutical composition, comprising at least one compound asclaimed in claim
 5. 23. A pharmaceutical composition, comprising atleast one compound as claimed in claim
 6. 24. A pharmaceuticalcomposition, comprising at least one compound as claimed in claim
 7. 25.A pharmaceutical composition, comprising at least one compound asclaimed in claim
 8. 26. A pharmaceutical composition, comprising atleast one compound as claimed in claim
 9. 27. A pharmaceuticalcomposition, comprising at least one compound as claimed in claim 10.28. A pharmaceutical composition, comprising at least one compound asclaimed in claim
 11. 29. A pharmaceutical composition, comprising atleast one compound as claimed in claim
 12. 30. A pharmaceuticalcomposition, comprising at least one compound as claimed in claim 13.31. A pharmaceutical composition, comprising at least one compound asclaimed in claim
 14. 32. A pharmaceutical composition, comprising atleast one compound as claimed in claim
 15. 33. A pharmaceuticalcomposition, comprising at least one compound as claimed in claim 16.34. A pharmaceutical composition, comprising at least one compound asclaimed in claim 17.